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    Published under the joint sponsorship of
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    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1986

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    1.1. Summary
         1.1.1. General
         1.1.2. Properties and analytical methods
         1.1.3. Sources; environmental transport and distribution
         1.1.4. Environmental levels and exposure
         1.1.5. Effects on organisms in the environment
         1.1.6. Metabolism
         1.1.7. Mode of action
         1.1.8. Effects on experimental animals and  in vitro 
                test systems
         1.1.9. Effects on human beings
         1.1.10. Therapy of poisoning
    1.2. Recommendations


    2.1. Chemical and physical properties
         2.1.1. Effects of light
         2.1.2. Effects of solutes and solvents
    2.2. Analytical methods


    3.1. Sources of pollution
    3.2. Environmental transport and distribution
         3.2.1. Distribution in air and water
         3.2.2. Distribution in food
    3.3. Bioaccumulation and degradation in the environment
    3.4. Exposure levels
         3.4.1. Exposure of the general population
         3.4.2. Occupational exposure


    4.1. Uptake
         4.1.1. Dermal uptake
         4.1.2. Gastrointestinal tract
         4.1.3. Inhalation
    4.2. Distribution and storage
         4.2.1. Experimental animal studies on distribution 
                and storage
    4.3. Biotransformation
         4.3.1. Mixed-function oxidases (MFOs)
        Oxidative desulfuration
        Oxidative  N - dealkylation

        Oxidative  O -dealkylation
        Oxidative de-arylation
        Thioether oxidation
        Side-chain oxidation
         4.3.2. Hydrolases
         4.3.3. Transferases
        Transferases handling primary metabolites
         4.3.4. Tissue binding
    4.4. Elimination
    4.5. Mode of action
         4.5.1. Inhibition of esterases
         4.5.2. Possible alkylation of biological macromolecules


    5.1. Aquatic organisms


    6.1. Effects on the nervous system
         6.1.1. Effects attributed to interaction with esterases
        Cholinergic effects
        Delayed neuropathic effects
         6.1.2. Behavioural and other effects on the nervous system
    6.2. Other effects
         6.2.1. Mutagenic and carcinogenic effects
         6.2.2. Teratogenic effects
         6.2.3. Effects on the immune system
         6.2.4. Effects on tissue carboxyesterases
         6.2.5. Sundry other effects of organophosphorus
        Effects on hormones
        Effects on the reproductive system
        Effects on the retina
        Porphyric effect
        Lipid metabolism
        Effects causing delayed deaths
        Selective inhibition of thermogenesis
    6.3. Factors influencing organophosphorus insecticide toxicity
         6.3.1. Dosage-effect
         6.3.2. Age and sex
         6.3.3. Nutrition
         6.3.4. Effects of impurities and of storage
        Impurities toxic in their own right
        Impurities potentiating the toxicity
                         of the major ingredient
         6.3.5. Effects of other pesticides and of drugs
         6.3.6. Species
         6.3.7. Other factors
    6.4. Acquisition of tolerance to organophosphorus
    6.5. Therapy of experimental organophosphorus poisoning
         6.5.1. Palliation
         6.5.2. Antagonism of effects of ACh
         6.5.3. Reactivation of inhibited AChE
         6.5.4. Efficacy of therapy


    7.1. Acute cholinergic poisoning
         7.1.1. Methods for assessing absorption and effects of 
                organophosphorus insecticides 
        Analysis of urine as a means of monitoring 
                         exposed populations 
        Biochemical methods for the measurement of 
        Electrophysiological methods for the study 
                         of effects 
         7.1.2. Monitoring studies
         7.1.3. Retrospective studies of populations exposed to 
                organophosphorus pesticides: acute and long-term 
    7.2. Other effects on the nervous and neuromuscular system due 
         to acute or long-term exposure 
         7.2.1. Delayed neuropathic effects
         7.2.2. Behavioural effects
    7.3. Effects on other organs and systems
    7.4. Treatment of organophosphate insecticide poisoning in man
         7.4.1. Minimizing the absorption
         7.4.2. General supportive treatment
         7.4.3. Specific pharmacological treatment
        Oxime reactivators
        Notes on the recommended treatment








Dr D. Ecobichon, Department of Pharmacology and Therapeutics,
   McGill University, Montreal, Quebec, Canada

Dr A.H. El-Sebae, Department of Pesticide Chemistry, Faculty
   of Agriculture, University of Alexandria, Alexandria, Egypt

Dr L. Ivanova-Chemishanska, Institute of Hygiene and Occupational 
   Health, Medical Academy, Sofia, Bulgaria  (Vice-Chairman)

Dr M.K. Johnson, Toxicology Unit, Medical Research Council
   Laboratories, Carshalton, Surrey, United Kingdom  (Rapporteur)

Dr S.K. Kashyap, National Institute of Occupational Health,
   Ahmedabad, India

Dr M. Lotti, Institute of Occupational Health, Padua, Italy

Dr L. Martson, All-Union Scientific Research Institute of the
   Hygiene and Toxicology of Pesticides, Polymers, and
   Plastics (VNIIGINTOX), Kiev, USSRa 

Dr U.G. Oleru, College of Medicine, University of Lagos,
   Lagos, Nigeria

Dr W.O. Phoon, Department of Social Medicine and Public
   Health, National University of Singapore, Outram Hill,
   Republic of Singapore  (Chairman)

Dr E. Reiner, Institute for Medical Research and Occupational
   Health, Zagreb, Yugoslavia

Dr A.F. Rahde, Ministry of Public Health, Porto Alegre, Brazil

Dr J. Sekizawa, National Institute of Hygienic Sciences,
   Tokyo, Japan


Mr R.J. Lacoste, International Group of National Associations
   of Pesticide Manufacturers (GIFAP), Brussels, Belgium

Dr W.O. Phoon, International Commission on Occupational
   Health, Geneva, Switzerland


Mme B. Bender, United Nations Environment Programme,
    International Register of Potentially Toxic Chemicals,
    Geneva, Switzerland

 Secretariat (contd.)

Dr J.R.P. Cabral, Unit of Mechanisms of Carcinogenesis,
   International Agency for Research on Cancer, Lyons, France

Dr K.W. Jager, International Programme on Chemical Safety,
   World Health Organization, Geneva, Switzerland  (Secretary)

Dr G.J. Van Esch, Bilthoven, The Netherlands  (Temporary

Dr C. Xintaras, Office of Occupational Health, World Health
   Organization, Geneva, Switzerland

a   Invited, but unable to attend.


    Every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors that may have occurred to the 
Manager of the International Programme on Chemical Safety, World 
Health Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes. 

                       *    *    *

    Detailed data profiles and legal files for most of the 
organophosphorus insecticides can be obtained from the 
International Register of Potentially Toxic Chemicals, Palais des 
Nations, 1211 Geneva 10, Switzerland (Telephone no.  988400 -


    A WHO Task Group on Environmental Health Criteria for 
Organophosphorus Insecticides was held in Geneva on 30 September - 
4 October 1985.  Dr K.W. Jager opened the meeting on behalf of the 
Director-General.  The Task Group reviewed and finalized the draft 
criteria document. 

    The drafts of this document were prepared by DR M.K. JOHNSON of 

     The efforts of all who helped in the preparation and 
finalization of the document are gratefully acknowledged. 

                         * * *

    Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA - a WHO Collaborating Centre for Environmental 
Health Effects.  The United Kingdom Department of Health and Social 
Security generously supported the cost of printing. 


    Following the Second World War, organochlorine pesticides made 
a major contribution to improvements in agricultural output and in 
the control of disease vectors.  While the persistence of these 
compounds after application was of considerable benefit to the 
user, it also introduced problems.  As these problems became more 
widely appreciated, insect pest control began to rely more on the 
anticholinesterase organophosphorus and carbamate ester pesticides.  
A large number of such esters have been introduced on the market, 
and a much greater number have been screened for pesticidal 
activity.  Unlike many environmental pollutants, pesticides are 
deliberately added to the environment and are devised to be lethal 

    It would not be possible to review the class of organo-
phosphorus insecticides in one document, because they are so 
numerous (more than 100) and cover a wide range of toxicity. 
However, because they have many properties in common, it was 
decided to prepare Organophosphorus Insecticides - A General 
Introduction to provide background information for brief 
Environmental Health Criteria documents on specific organo-
phosphorus insectides. 

    In addition to the literature cited in the text, much useful 
information has been obtained from the following works of 
reference: CEC (1977), Kagan (1977, 1985), Hayes (1982), Medved & 
Kagan (1983), Worthing (1983), Mel'nikov et al.  (1985), and Farm 
Chemicals Handbook (1985). 

    For the purposes of this document, the word "insecticide" is 
used more broadly than the strict zoological classification of 
insects.  Many have some selectivity for particular classes of 
pests (mites, aphids, etc.) but, with 2 exceptions, all the 
compounds covered in the introductory document exert their primary 
effect by inhibiting the vital acetylcholinesterase of the nervous 

    Non-ester organophosphorus compounds, having herbicidal 
activity are not considered, but the herbicide amiprophos ( O -
ethyl- O -4-methyl-6-nitrophenyl  N- isopropyl phosphoramidothioate) 
and defoliants related to DEF ( S,S,S -tri- n -butylphosphoro-
trithioate) are included because they, in common with 
organophosphorus insecticides, are esters and possess the ability 
to inhibit tissue esterases and can cause cholinergic and/or 
delayed neuropathic responses. 

1.1.  Summary

1.1.1.  General

    At least 100 organophosphorus insecticides have been reviewed 
by WHO for consideration as agents for the control of disease 
vectors.  A large number have been reviewed by the FAO/WHO Joint 
Meetings on Pesticide Residues.  Unlike many compounds scrutinized 
by the IPCS, these compounds are designed to be toxic for certain 
pests and are added deliberately to the environment.  However, they 
have a wide range of acute toxicity for experimental animals, and 
it is impossible to review the whole class in a single 
comprehensive document.  Thus, the purpose of this document is to 
give a framework of information and understanding with suitable 
illustrations that will provide the background to brief 
Environmental Health Criteria documents on specific insecticides. 

    For the purposes of this document, the word "insecticide" is 
used in a broad sense and covers miticides, acaricides, etc.  A few 
organophosphorus insecticide compounds, with a toxicological mode 
of action similar to that of the insecticides, are mentioned, 
though they are intended for use as herbicides. 

1.1.2.  Properties and analytical methods

    Organophosphorus insecticides are normally esters, amides, or 
thiol derivatives of phosphoric, phosphonic, phosphorothioic, or 
phosphonothioic acids.  Most are only sightly soluble in water and 
have a high oil-to-water partition coefficient and low vapour 

    Physical and chemical data are not given in this introduction 
but may be obtained from other sources including other WHO 
publications, IRPTC profiles, and the handbooks included in the 
list of references.  A principal source for analytical methods is 
provided by the Codex Alimentarius Commission of the Joint FAO/WHO 
Food Standards Programme. 

1.1.3.  Sources; environmental transport and distribution

    While there has been a considerable increase in the annual use 
of organophosphorus insecticides for crop protection since 1970, 
the overall increase has been less since the early 1980s. However, 
new uses and formulations have been introduced.  In particular, 
parathion and malathion are widely used.  Only a few of the less 
hazardous organophosphorus insecticides have been evaluated for 
disease vector control, and these contribute a very small 
percentage to total usage. 

    With the exception of dichlorvos, most organophosphorus 
insecticides are of comparatively low volatility.  Dispersion of 
spray droplets by wind is possible, but, in general, only small 
amounts are likely to be distributed in this way. 

    The principal route of degradation in the environment seems to 
be hydrolysis.  In soil and the aqueous environment, the survival 
time and the possibility of distribution in water may be influenced 
by light intensity and pH.  Most organophosphorus insecticides are 
more stable in the pH range that may be encountered in the 
environment (pH: 3 - 6), than at neutral pH. The influence of 
microbiological factors in the degradation of these insecticides in 
soil and water may be considerable. Different climatic conditions, 
especially temperature and humidity, before, during, and after 
spraying may influence the survival time markedly. 

1.1.4.  Environmental levels and exposure

    Apart from occupationally exposed workers or populations 
exposed as a result of disease-vector control programmes, marked 
exposure of the general population is not expected.  While exposure 
via foodstuffs is sometimes monitored and controlled, there is 
little information about exposure via groundwater, which may reach 

1.1.5.  Effects on organisms in the environment

    Only a little information is available on the toxicity of 
organophosphorus insecticides for fish and aquatic insects.  The 
mechanism of toxicity has not been shown to be necessarily an 
anticholinesterase effect.  Lethal concentrations derived from 48-h 
exposures in clean laboratory water may be artificially low 
compared with exposure in environmental waters. 

1.1.6.  Metabolism

    The metabolic fate of organophosphorus insecticides is 
basically the same in insects, animals, and plants.  Uptake in 
animals and insects may occur through the skin, respiratory system, 
or gastrointestinal tract.  While uptake of active ingredient 
through the skin from powdered or granulated formulations may be 
relatively inefficient, the presence of aqueous dispersing agents 
or organic solvents in a spray concentrate or formulation may 
greatly enhance uptake.  Although the actual exposure of the 
respiratory system may not be as high as the exposure of skin in 
unprotected persons, the efficiency of absorption might be high. 

    Metabolism occurs principally by oxidation, hydrolysis by 
esterases, and by transfer of portions of the molecule to 
glutathione.  Oxidation of organophosphorus insecticides may result 
in more or less toxic products.  In general, phosphorothioates are 
not directly toxic but require oxidative metabolism to the proximal 
toxin.  Most mammals have more efficient hydrolytic enzymes than 
insects and, therefore, are often more efficient in their 
detoxification processes.  Birds usually have lower esterase 
activity than mammals.  The glutathione transferase reactions 
produce products, that are, in most cases, of low toxicity.  
Hydrolytic and transferase reactions affect both the thioates and 
their oxons.  Numerous conjugation reactions follow the primary 
metabolic processes, and elimination of the phosphorus-containing 

residue may be via the urine or faeces. Some bound residues remain 
in exposed animals.  Binding seems to be to proteins, principally, 
and the turnover appears to be related to the half-life of these 
proteins.  There are limited data showing that incorporation of 
residues into DNA occurs only in trace amounts and not by direct 
alkylation, such as might be believed to be associated with genetic 

1.1.7.  Mode of Action

    Organophosphorus insecticides exert their acute effects in both 
insects and mammals by inhibiting acetylcholinesterase (AChE) in 
the nervous system with subsequent accumulation of toxic levels of 
acetylcholine (ACh), which is a neurotransmitter.  In many cases, 
the organophosphorylated enzyme is fairly stable, so that recovery 
from intoxication may be slow. 

    Because of the greater stability of organophosphorylated AChE 
compared with carbamylated enzyme, the ratio of the dose of an 
organophosphorus insecticide required to produce mortality and that 
which produces minimum symptoms of poisoning is substantially less 
than the same ratio for carbamate insecticides. Reactivation of 
inhibited enzyme may occur spontaneously, rates of reactivation 
depending on the species and the tissue, as well as on the chemical 
group attached to the enzyme.  In particular, in most mammals, 
dimethylphosphorylated AChE undergoes substantial spontaneous 
reactivation within one day, which facilitates recovery from 
intoxication.  Reactivation of inhibited AChE may be induced by 
some oxime reagents, and this fact provides opportunities for 
therapy.  Response to reactivating agents declines with time, and 
this process is called "aging" of the inhibited enzyme. 

    Delayed neuropathy is initiated by attack on a nervous tissue 
esterase distinct from AChE.  The target has esterase activity and 
is called neuropathy target esterase (formerly neurotoxic esterase 
(NTE)).  The disorder develops not because of loss of esterase 
activity but because of some overall change brought about in the 
protein molecule resulting from the process of aging of inhibited 
NTE: catalytic activity of NTE reappears in the nervous tissue, 
even during the period of development of neuropathy.  Some 
organophosphinates, sulfonyl fluorides, and carbamates may inhibit 
NTE and act as protective agents, covering the target with 
molecules that cannot engage in the aging reaction.  The 
structure/activity relationships for inhibitors of NTE differ from 
those for AChE, so that pesticides designed as inhibitors of AChE 
may be less effective as inhibitors of NTE, and may have low 
neuropathic potential. 

    The rate of reaction of one chosen organophosphorus insecticide 
with AChE was many orders higher than its rate of alkylation of the 
test nucleophile, 4-nitrobenzylpyridine.  On this limited data, it 
seems unlikely that alkylation of biological macromolecules by 
organophosphorus insecticides would occur in mammals. 

1.1.8.  Effects on experimental animals and  in vitro  test systems

    The acute toxicity of organophosphorus insecticides is due to 
their anticholinesterase action.  The oral and dermal LD50s for 
many compounds are listed in Annex III.  It cannot be over-
emphasized that these numbers are not precise, and substantially 
different values may be reported from different sources, even when 
the factors of species, age, and sex have been standardized.  These 
LD50 values range from less than 10 mg/kg body weight to more than 
3000 mg/kg for the oral route and, for most compounds, are 
significantly higher for the dermal route. 

    For single exposures, a dose-effect relationship exists between 
the dose and the severity of symptoms, and, also, the degree of 
AchE inhibition in nervous tissue.  The inhibition of blood-AChE 
may not be similar to that in nervous tissue.  Effects on plasma-
pseudocholinesterase (pseudoChE) are dose-related but are not 
correlated with intensity of symptoms.  For some insecticides, 
pseudocholinesterase is more sensitive to inhibition than AChE, 
but, for others, the converse is true. 

    The majority of organophosphorus insecticides do not cause 
delayed neuropathy in test animals at doses up to the LD50.  When a 
dose is above the LD50 but is given in conjunction with therapy 
against anticholinesterase effects, more compounds have been shown 
to cause clinical neuropathy and, for others, substantial, but sub-
threshold, effects on NTE have been shown.  For other compounds, 
only slight effects on NTE have been shown, even at doses much 
above the normally lethal dose.  The results of dose-response 
studies have shown that at least 70% inhibition of NTE in the brain 
and spinal cord is required for initiation of delayed neuropathy in 
adult hens, the usual test species.  This threshold is not so 
clearly defined for other species, and laboratory rodents do not 
display clinical signs of neuropathy after a single dose.  No 
marked change in the threshold level of inhibition has been shown 
between adult hens of different strains, but more information is 

    Short- and long-term toxicity studies have been carried out. 
While typical cholinergic intoxication only occurs when nervous 
tissue AChE is substantially inhibited, the converse may not be 
true in cases of long-term exposure because of the development of 
tolerance, which is believed to be due, in part, to changes in some 
cholinergic receptors.  NTE appears to be synthesized continuously.  
Consequently, continuous administration of an organophosphorus 
compound does not necessarily lead to a continuous increase in the 
level of inhibited NTE; the level may tend to reach equilibrium 
below the threshold required to initiate neuropathy.  With 
continuous administration of neuropathic organophosphorus compounds 
for up to 90 days, a peak level of about 50% inhibition of NTE must 
be maintained to initiate neuropathy. 

    Acceptable daily intakes (ADIs) have been established as a 
result of the evaluation of data by the FAO/WHO Joint Meetings on 
Pesticide Residues (JMPR) (Annex II).  ADIs are derived from 
measurements or estimates of the highest dietary level that does 

not cause significant changes in any measured variable, the most 
sensitive of which is usually the AChE or pseudoChE activity in 
blood.  For no-observed-adverse-effect levels, see Annex III. 

    A variety of behavioural changes have been seen in response to 
single or long-term dosing, but, in nearly all of the cases 
reported, there was concomitant inhibition of AChE, though not 
necessarily up to levels associated with typical signs of 
poisoning; dose-response relationships have not always been 
established.  So far, behavioural tests have not proved adequate to 
screen for organophosphate intoxication. 

    Effects on tissue carboxyesterases may be caused by some 
organophosphorus insecticides at doses below those affecting AChE 
or ChE.  Apart from the delayed neuropathic effect arising from the 
inhibition and aging of NTE, inhibition of other carboxyesterases 
is not known to have any direct toxic effects. However, prior 
inhibition of carboxyesterases may potentiate the toxicity for 
mammals of pesticides, such as malathion and most pyrethroids, 
which are normally detoxified by tissue esterases. 

    Various organophosphorus pesticides have been reported to show 
positive responses in  in vitro mutagenicity tests, but full 
experimental details of the tests and control conditions have not 
always been available.  It can be concluded that some agents are 
weakly mutagenic  in vitro.  Six organophosphorous pesticides have 
been evaluated for mutagenic and carcinogenic potential by the 
International Agency for Research on Cancer (IARC).  In several 
cases, the conclusion was that acceptable tests had been performed 
with no evidence of carcinogenic potential, while, in others, the 
conclusion was that there was "limited evidence consisting of very 
small effects above the control background levels in lifetime 

    Many organophosphorus insecticides are embryotoxic at doses 
that are toxic for the mother.  Teratogenic effects have been 
reported for trichlorphon in pigs, but few teratogenic effects have 
been reported for other compounds. 

    Some deficiency in immune responses has been reported in 
animals dosed with quantities of organophosphorus insecticides that 
depressed AChE levels, but not at doses that did not affect AChE. 

    Several other toxic effects have been claimed after single or 
repeated doses of individual compounds, but these effects have not 
been reported for a range of the insecticides.  Tissues and systems 
reported to have been affected include the retina, lung, and 
reproductive system. 

    Differences in toxic dose, but not in the mode of toxicity, 
have been reported in animals according to species, age, sex, and 
nutritional state.  All these factors influence the status of a 
variety of metabolizing enzymes in the body, but there is no steady 
observable general trend towards increased or decreased toxicity in 
response to variations in these variables. 

    Impurities may be found in either technical grade or formulated 
organophosphorus insecticides.  The impurities arise during the 
synthesis or storage of technical or formulated material.  The 
levels of impurities may differ according to the route of synthesis 
chosen, the formulating ingredients added, or the storage 
conditions.  Impurities may be toxic in their own right, toxic as 
potentiators that block the metabolic degradation of the major 
toxic ingredient, or not toxic. 

1.1.9.  Effects on human beings

    Signs and symptoms of acute intoxication by organophosphorus 
insecticides include muscarinic, nicotinic, and central nervous 
system (CNS) manifestations.  Symptoms may develop rapidly, or 
there may be a delay of several hours after exposure before they 
become evident.  The delay tends to be longer in the case of more 
lipophilic compounds, which also require metabolic activation. 
Symptoms may increase in severity for more than one day and may 
last for several days.  In severe cases, respiratory failure is a 
dominant effect. 

    In mild cases, or where the compound is disposed of rapidly, 
symptoms may regress quite quickly, though depressed blood-ChE 
levels may take several weeks to return to normal levels.  There 
appear to be few long-term effects after acute intoxication, though 
weakness and fatigue may persist for several months. 

    Several methods are available for measuring exposure to, and 
effects of, organophosphorus insecticides, and the combined use of 
all methods is valuable, both in diagnosis of poisoning and in 
determination of exposure.  Standard methods for measuring dermal 
exposure have been described in technical reports of WHO. 
Determination of urinary metabolites provides an indication of 
exposure, and analysis of serial samples is more valuable than a 
single sample.  Methods for the determination of residues are 
available, and the Report of the Codex Alimentarius Commission of 
FAO/WHO provides details and critical assessment of methods.  In 
general, it is not possible to relate the concentration of urinary 
metabolites to the level of intoxication, though some guidelines 
may be developed in connection with the controlled use of any 
single organophosphorus pesticide. 

    Levels of erythrocyte- or whole blood-AChE are a satisfactory 
guide to the level of acute intoxication.  Plasma or serum levels 
of pseudoChE are only useful as indicators of exposure.  It is 
essential that skin is cleansed carefully before taking blood 
samples for analysis.  Both enzymes are measurable with good 
accuracy using a standard kit suitable for field work and 
purchaseable from the World Health Organization; paper tests for 
screening purposes have been described.  Depression of AChE or 
pseudoChE below about 75% of pre-exposure levels is generally 
accepted as indicating that a hazard exists, and that workers 
should be removed from all contact with the specific insecticide 
until the levels recover.  Signs of poisoning do not usually appear 
until blood levels of AChE are below 50%, while severe poisoning is 

usually associated with depression to below 30%. While measurement 
of AChE is useful in preventive work and in diagnosis, measuring 
the levels of blood-AChE as intoxication or therapy progress is of 
less value.  Electromyographic (EMG) monitoring of occupationally 
exposed workers has been reported to be valuable in assessing 
hazard, but there is some dispute, and no certain characteristic 
change in EMG has been agreed.  Further work under controlled 
exposure conditions with parallel chemical, biochemical, and 
clinical monitoring is desirable. 

    In all cases of intoxication, labels from containers should be 
preserved, but these may be misleading.  Whenever possible, a 
sample of the incriminating agent should be stored carefully, and 
tissue samples should be taken to aid in the identification of the 
active agent. 

    Delayed neuropathies in occupationally exposed workers have 
been reported for only a few of the many currently used 
organophosphorus insecticides.  For one pesticide, methamidophos, 
the syndrome has not been reproduced in experimental animals. There 
is no specific treatment for neuropathy, though physiotherapy may 
limit the degree of muscle wasting that follows denervation.  In 
mild cases, some slow improvement can occur, but, in more severe 
cases, the defects are permanent.  The NTE of human tissue appears 
to be similar to the NTE of experimental animals, and 
extrapolations from results of laboratory tests in animals may be 
of value.  Samples of blood lymphocytes provide an accessible 
source of NTE for monitoring purposes, though there is some 
uncertainty about the stability of NTE in stored lymphocytes. 

    Continuous long-term exposure to high levels of 
organophosphorus insecticides may precipitate typical cholinergic 
symptoms, though most of the compounds do not accumulate 
extensively in the body.  Removal from exposure until AChE levels 
return to pre-exposure levels appears to be an adequate health 
precaution.  There is no clear evidence of adverse effects on 
health from long-term exposure to organophosphorus insecticides at 
levels that do not affect AChE. 

    There is limited anecdotal evidence of behavioural effects 
arising from long-term, or occasionally even a single, exposure to 
one or other organophosphorus insecticide.  The reports are 
difficult to evaluate and are often complicated by the presence of 
other factors, such as endogenous disorders and exposure to other 

1.1.10.  Therapy of poisoning

    Therapy of AChE poisoning by organophosphates may be graded 
according to the severity of intoxication.  Effective therapy for 
most compounds appears to consist of co-administration of atropine 
with an oxime reactivating agent plus diazepam.  Useful physical 
measures include the maintenance of clear airways plus artificial 
respiration.  Efficacy of oximes may decline as the inhibited AChE 
ages.  Oxime therapy may continue to be effective in reactivating 

AChE, freshly inhibited by inhibitor released from storage in body 
depots, long after the bulk of the inhibited enzyme has aged. 

    There is no known therapy for severe delayed neuropathy.  Mild 
neuropathies tend to regress, presumably due to some regeneration 
or adaptation of peripheral nerves. 

1.2.  Recommendations

    Recommendations for further work on individual organophosphorus 
insecticides have been made in the Monographs published in the 
Technical Report Series of the JMPR and in some reports from IARC.  
Apart from these, some general and specific recommendations are: 

1.  More up-to-date information should be obtained on the world-
wide production and uses of organophosphorus pesticides. 

2.  Information is needed on environmental pathways, 
concentrations, and distribution of organophosphorus pesticides. 

3.  There is a need for more information on the occurrence and fate 
of organophosphorus insecticides in surface water, soil, and 
groundwater, and on their impact on plants, invertebrates, and 

4.  Further studies are necessary on the occurrence of 
organophosphorus insecticides in the different food chains 
(bioaccumulation) and in the food and drinking-water of man (market 
basket or total-diet studies), in order to estimate the daily 
exposure of the population. 

5.  More information should be obtained on the acute and long-term 
toxicity of certain organophosphorus insecticides for aquatic and 
terrestrial organisms. 

6.  Apart from a number of studies on human volunteers and a number 
of accidents, there is little information on the effects of human 
exposure to organophosphorus insecticides.  More information should 
be collected to evaluate the risks of human exposure to these 

7.  Further work should be done to develop more adequate analytical 
methods (i.e., faster procedures and simpler equipment) to 
determine organophosphorus residues in biological material (urine, 
blood), and also in food.  In this connection, the work of the 
Codex Alimentarius Commission is noted.  Also, further work is 
required to develop less hazardous reagents for these analyses. 

8.  Exposure and health variables in workers exposed occupationally 
to only one organophosphorus insecticide at a time should be 
carefully monitored.  This is an essential background to the more 
complex problem of assessment of workers exposed to a variety of 
pesticides.  Procedures should include validation of methodology of 
chemical, biochemical, behavioural, and electrophysiological tests 

and should demonstrate the variation in results in both pre-
exposure and post-exposure situations. Adequate groups of matched 
controls should also be studied. 

9.  Measurements of NTE responses in toxicity tests on hens should
be evaluated.  The validity and variability of such tests should
be established.  Further studies are needed to establish whether
NTE in lymphocytes and/or platelets should be measured in people
exposed to certain organophosphorus insecticides.

10.  Enzymes that hydrolyse organophosphates play a role in 
detoxifying some organophosphorus insecticides.  Further studies 
are required to establish whether the activity of these enzymes in 
plasma is a good guide to the total hydrolytic capacity of the 
whole body. 

11.  Liasion between National Poison Control Centres and experts 
studying the effects of organophosphorus insecticides should be 
improved.  Preservation of blood, urine, and gastric lavage fluids 
might assure the identity of an intoxicating agent.  Also, 
preservation of autopsied nervous tissue from fatal cases may 
facilitate laboratory studies on the dose-response of human nervous 
tissue NTE.  Such studies may indicate the threshold of NTE 
inhibition that might be expected to initiate delayed neuropathy in 

12.  Information should be obtained concerning the changes in 
toxicity due to impurities that can arise in pesticides as a 
consequence of different manufacturing processes, the use of 
formulating ingredients, and improper storage. 

13.  Consideration should be given to possible conflicts of 
therapeutic procedures recommended for the treatment of poisoning 
by other classes of pesticide when dealing with severe intoxication 
by mixtures of such compounds with organophosphorus insecticides. 

14.  Users should be encouraged to be aware of the necessity to
establish a safe re-entry period according to local conditions.


2.1  Chemical and Physical Properties

    Various structures of organophosphorus insecticides are 
illustrated in Table 1.  The compounds are normally esters, amides, 
or thiol derivatives of phosphoric or phosphonic acid: 

                      R1    O (or S)
                        \  ||
                           P -- X

where R1  and R2  are usually simple alkyl or aryl groups, both of 
which may be bonded directly to phosphorus (in phosphinates), or 
linked via -O-, or -S- (in phosphates), or R1  may be bonded 
directly and R2 , bonded via one of the above groups (phosphonates).  
In phosphoramidates, carbon is linked to phosphorus through an -NH 
group.  The group X can be any one of a wide variety of substituted 
and branched aliphatic, aromatic, or heterocyclic groups linked to 
phosphorus via a bond of some lability (usually -O- or -S-) and is 
referred to as the leaving group.  The double-bonded atom may be 
oxygen or sulfur and related compounds would, for example, be 
called phosphates or phosphorothioates (the nomenclature 
"thiophosphate" or "thionophosphate" is now less used). 

    The P=O form of a thioate ester may be referred to as the oxon, 
and this is often incorporated in the trivial name (e.g., parathion 
is the parent P=S compound of paraoxon). 

    The variations in the phosphorus group for the insecticides 
that have been developed, are shown in Table 1 together with the 
common or other names for some pesticides falling into this 
classification.  The complete structure and names for all the 
organophosphorus compounds mentioned are listed in Annex I.  It can 
be seen that, in terms of numbers of commercial compounds, there 
are 3 main groups: phosphates (without a sulfur atom), 
phosphorothioates (with one sulfur atom), and phosphorodithioate 
(with 2 sulfur atoms).  Since the P=S form is intrinsically more 
stable, many insecticides are manufactured in this form which can 
be converted to the biologically active oxon in tissues.  The 
manner of this conversion is discussed in section 4. 

    Specific biotransformation of substituent groups in R1 , R2 , and 
X may occur, and this is also considered later.  Cleavage of the 
direct carbon-to-phosphorus bonds of phosphonates and phosphinates 
may occur to a small extent in the final stages of biodegradation, 
but is probably insignificant as far as biological effects are 

Table 1.  Variations in the chemical structure of organophosphorus insecticides
Type of phosphorus group        Outline of structure   Common or other name
Phosphate                              O               chlorfenvinphos, crotoxyphos, dichlorvos,
                                       ||              dicrotophos, heptenphos, mevinphos, monocroto-
                                (R-O)2-P-O-X           phos, naled, phosphamidon, TEPP, tetrachlor-
                                                       vinphos, triazophos

 O -alkyl phosphorothioate              O               amiton, demeton-S-methyl, omethoate, oxydemeton-
                                       ||              methyl, phoxim, vamidothion

                                       S               azothoate, bromophos, bromophos-ethyl, chlor-
                                       ||              pyriphos, chlorpyriphos-methyl, coumaphos, dia-
                                (R-O)2-P-O-X           zinon, dichlofenthion, fenchlorphos, fenitro-
                                                       thion, fenthion, iodofenphos, parathion, para-
                                                       thion-methyl, pyrazophos, pyrimiphos-ethyl,
                                                       pyrimiphos-methyl, sulfotep, temephos, thionazin

Phosphorodithioate                     S               amidithion, azinophos-ethyl, azinophos-methyl,
                                       ||              dimethoate, dioxathion, disulfoton, ethion,
                                (R-O)2-P-S-X           formothion, malathion, mecarbam, menazon, meth-
                                                       idathion, morphothion, phenthoate, phorate,
                                                       phosalone, phosmet, prothoate, thiometon

 S- alkyl phosphorothioate                              profenofos, trifenofos
                                R     O
                                  \   || 
                                   S  ||

 S- alkyl phosphorodithioate         S                  prothiofos, sulprofos
                               R-S  ||

Phosphoramidate                        O               cruformate, fenamiphos, fosthietan

Table 1.  (contd.)
Type of phosphorus group        Outline of structure   Common or other name
Phosphorotriamidate                    O               triamiphos

Phosphorothioamidate                    O              methamidophos

                                       S               isofenphos

Phosphonate                          O                 butonate, trichlorfon
                                 RO  ||

Phosphonothioate                       S               EPN, trichlornat, leptophos, cyanofenphos
                                  R-O  ||
    In order to be useful, these compounds must be reasonably 
stable at neutral pH, since many are formulated as concentrates in 
oil, in water-miscible solvents such as ethylene glycol monomethyl 
ether, or are absorbed on to inert granules for application 
directly or after dispersion in water.  However, nearly all are 
rapidly hydrolysed by alkali and many are also unstable at pH 
levels below 2.  Phosphoramidates are hydrolysed in an acid-
catalysed reaction, even at pH 4 - 5, and, since acid is produced, 
decomposition tends to accelerate due to autocatalysis. 

    Oxidation of phosphorothioates to phosphates (-P=S --> -P=O) 
is potentially dangerous, since the phosphates are more volatile 
and are directly toxic agents. This can occur by oxidation of 
stored products at elevated temperatures. The enzymatic catalysis 
of this reaction is considered in section 4. 

    Various uncatalysed isomerizations are reported to occur under 
forcing conditions of heating at over 100 °C for many hours in the 
laboratory (Dauterman, 1971).  Also, an isomerization associated 
with considerable toxic hazard has been observed during the storage 
of some formulations of malathion, particularly under warm humid 
climatic conditions: 

                            S               O
                            |               ||
                    (CH3O)2-P-SR --->    CH3S-P-SR

The  S- methyl derivatives, formed from malathion by this 
isomerization, potentiate the toxicity of malathion markedly 
(section 6.3.4).  The isomerization reaction is not completely 
understood, but it has been shown to be catalysed by dimethyl 
formamide under laboratory conditions (Eto & Ohkawa, 1970).  It is 
not clear whether all alkyl phosphorothioates are subject to this 
reaction, but it probably occurs most readily with the methyl 
esters and may be influenced by the formulating agents.  The hazard 
resulting from isomerization will depend, not only on the extent of 
the reaction and the intrinsic toxicity of the product, but also on 
the manner of metabolic disposal of the parent compound (see 
discussion in section 7). 

    Besides the various effects of heat and air noted above, both 
light and solvent may influence the stability of these 
organophosphorus compounds. 

2.1.1  Effects of light

    Parathion was one of the first organophosphorus compounds in 
which the anticholinesterase activity, as measured  in vitro, was 
shown experimentally to increase during exposure to ultraviolet 
radiation (UVR) and sunlight.  However, the acute toxicity of 
parathion decreased under UVR, although the  in vitro  
anticholinesterase activity increased as the result of the 
formation of more polar products; the metabolites were identified 

as paraoxon and the  S- ethyl and  S -phenyl isomers of parathion, 
together with unknown products (Dauterman, 1971).  This study 
showed that UVR is able to oxidize as well as isomerize parathion.  
When parathion-methyl was given the same UVR treatment, only the 
methyl homologue of paraoxon was found.  In a similar study, in 
which EPN was exposed to UVR, the oxygen analogue of EPN and 
 p -nitrophenol were found together with unidentified resins, 
also indicating cleavage of the P-O-aryl bond.  Studies with 7 
organophosphorus pesticides containing sulfur in a thioether group 
indicated that exposure to UVR (254 nm) resulted in a variety of 
oxidation products.  With phorate, disulfoton, and thiometon, the 
corresponding sulfoxides and sulfones were identified as products 
of UVR.  With thiometon, evidence of oxidation of the thiono sulfur 
was also obtained.  In all 7 cases, the oxidation products were 
more acutely toxic than the parent compound.  Exposure of a 
carbethoxy analogue of mevinphos to UVR results in another type of 
photoisomerization. Starting with either the cis- or the trans-
isomer, or a mixture of the isomers, and exposing the compounds to 
UVR, results in a mixture of approximately 30% of the cis- and 70% 
of the trans-isomer; in all cases, the trans-isomer was 
predominant. When chlorpyrifos is exposed to UVR or sunlight, it 
undergoes hydrolysis in the presence of water to liberate 3,5,6-
trichlor-2-pyridinol, which then undergoes complete 
photodechlorination with the formation of diols, triols, and 

2.1.2  Effects of solutes and solvents

    The hydrolysis of organophosphorus compounds is influenced by 
solutes, e.g., some amino acids, hydroxylammonium derivatives; 
metal ions such as Cu++  act as catalysts. 

    Solvents used in formulating organophosphorus compounds to 
obtain properties that will increase the chances of contact between 
the insecticide and the target organism, influence their stability.  
It has been found that dimethoate in certain hydroxylic solvents, 
particularly 2-alkoxyethanols, increased in toxicity on storage 
(Casida & Sanderson, 1963).  The acute oral LD50 for rats decreased 
from 150 - 250 mg/kg body weight to 30 -40 mg/kg, after 7 months 
storage at normal temperatures.  Studies indicated that many 
reaction products were formed in the presence of methylcellosolve.  
The degradation involved hydrolysis of the amide bond, hydrolysis 
of ester groups, and loss of the thiono group.  The most toxic 
fraction was identified as dimethoate with probably one, but 
possibly both, of the methyl groups replaced by 2-methoxyethyl 
groups.  No evidence was obtained for the formation of pyro- 
phosphates.  In the same study, the toxicity of a few other 
phosphorothioate compounds was also found to increase in the 
presence of 2-methoxyethanol. 

    Another type of reaction occurs when organophosphorus compounds 
containing a sulfide group (R-S-R) are stored undiluted or in an 
aqueous solution.  Heath & Vandekar (1957) observed that a 1% 
solution of demeton- S -methyl increased in toxicity spontaneously 
at 35 °C during the course of one day.  This increase was found to 
be due to the formation of a transalkylated sulfonium derivative, 

the toxicity of which was more than 1000 times that of the parent 
compound.  A similar reaction has also been shown to take place 
with demeton-O (phosphorothioic acid,  O,O -diethyl  O -[2-
(ethylthio)-ethyl] ether: 


Samples of demeton-S-methyl that have been stored for a few months 
may contain up to 4% of the sulfonium compound.  The 
transalkylation reaction is extremely rapid with demetonmethyl, but 
slower with demeton. 

2.2  Analytical Methods

    Procedures consist of sampling, extraction, clean-up of 
extract, and determination of compounds.  Different procedures are 
required for the lipophilic alkali-labile parent pesticides and for 
residues that may be mainly stable non-lipophilic hydrolysis 
products.  Procedures for the determination of pesticide residues 
(not only organophosphorus insecticides) are discussed in the 
Report of a Joint FAO/WHO Course (Ambrus & Greenhalgh, 1984). 
Separation and clean-up usually involve partition between solvents 
and chromatography.  Detection may be by partially specific colour 
reagents or by enzyme inhibition tests applied to spots on thin-
layer chromatographic plates (Stefanac et al., 1976) or by 
formation of volatile derivatives suitable for detection by gas 
chromatography (Shafik et al., 1973).  Diazopentane has been 
recommended as a reagent that is less toxic and less difficult to 
handle than diazomethane which is often used, but not all workers 
regard the modification as satisfactory (Drevenkar et al., 1979). 
The hazard of using the volatile and highly carcinogenic 
diazomethane as a laboratory reagent should be recognized. 

    Methods for the the determination of residues of many 
individual pesticides are given by the Codex Alimentarius 
Commission (1984). 


3.1  Sources of Pollution

    Organophosphorus pesticides are mainly used in crop protection. 

    The world-wide consumption of these compounds from 1974-83 is 
shown in Table 2.  Only parathion and malathion can be shown 
separately from the other organophosphorus pesticides.  The 
information is incomplete since, for example, the USA and some 
other countries and regions do not report figures for every year. 
However, comparison of the figures given on a yearly basis gives an 
idea of the magnitude of the consumption and distribution of the 
organophosphorus pesticides throughout the world. 

    All organophosphorus pesticides are subject to degradation by 
hydrolysis yielding water-soluble products that are believed to be 
non-toxic at all practical concentrations.  The toxic hazard is 
therefore essentially short-term in contrast to that of the 
persistent organochlorine pesticides, though the half-life at 
neutral pH may vary from a few hours for dichlorvos to weeks for 
parathion.  At the pH of slightly acidic soils (pH 4 - 5), these 
half-lives will be extended many-fold.  However, constituents of 
soil and of river water may themselves catalyse degradation. 

3.2  Environmental Transport and Distribution

3.2.1  Distribution in air and water

    With the exception of dichlorvos, most organophosphorus 
pesticides are of comparatively low volatility.  Aerial sprays of 
dispersions of organophosphates may be spread by wind, but no 
evidence of contamination beyond limits of 1 - 2 km from the 
spraying source has been noted. 

    Three sources of entry into water are possible.  One is from 
industrial waste or effluent discharged directly into water.  A 
second is by seepage from buried toxic wastes into water supplies.  
Neither of these should be tolerated, since prior treatment of the 
waste with alkali (or acid in cases such as diazinon) followed by 
neutralization can destroy the toxic agent. Contamination of 
running water directly or from run-off during spraying operations 
can occur.  No studies on the degradation of organophosphorus 
pesticides in running water have been noted.  In static water, in a 
simulated aquatic environment, there is evidence of the 
contributions of light, suspended particulates, and bacteria to 
degradation.  Thus, the degradation of fenitrothion in lake water 
under illumination occurred with a half-life of about 2 days, 
compared with 50 days in the dark (Greenhalgh et al., 1980).  
Furthermore, Drevenkar et al. (1976) concluded that, though 
temperature and pH were major factors controlling the rate of 
hydrolysis of dichlorvos in water, large differences in the half-
life of this pesticide in different river waters must be attributed 
to microbiological factors. 

Table 2.  Consumption of organophosphorus insecticides (in 100 kg)a 
Country       Parathion                         Malathion                       Other organophosphorus
              1974    1981     1982    1983     1974    1981    1982    1983    1974    1981     1982     1983
              -76                               -76                             -76         

 Burundi                                                                        3
 Egypt        397                               3573    2080                    54 267  7200
 Gambia               120                                                               1000     477      350
 Madagascar           2
 Mauritania                                     50                              107
 Niger                                                  694             263     151     170               45
 Rwanda               1        2       3
 Sierra Leone                                   40
 South Africa                                                                   24 083
 Sudan                                                                          6787
 Swaziland                                                                      17
 Zimbabwe             215              450              91              10              3018

 North/Central America

 Bermuda                                        7                               2
 Canada       238                               2398                            11 519
 Cuba                                                                           22 667
 El Salvador  4000                              50                              357
 Guatemala    7704                              1010
 Honduras                                               391             414
 Mexico       46 000  50 000   48 000  48 000   3452    12 000  18 000  5000    21 812  54 520   46 350   48 300
 Mont Serrat                                            1       1                       1        1
 USA                  115 000  110 000                  15 000  15 000                  190 000  175 000

 South America

 Argentina            1650     4750                     2280    2350            2993    8340     15 560
 Guyana                                                         52                               60
 Surinam                                                28                              712
 Uruguay      10      105      78      179      45              91      47      201     415      344      735

Table 2.  (contd.)
Country       Parathion                         Malathion                       Other organophosphorus
              1974    1981     1982    1983     1974    1981    1982    1983    1974    1981     1982     1983
              -76                               -76                             -76         

 Bahrain      5
 Bangladesh                                                                             620      649
 Brunei                                                                                 8        6        20
 Burma                                          34 317
 Cyprus       222     1782     842              89      255     212             132     534      591
 Hong Kong                                                                      1000    414      604      536
 India        9657    20 920   30 300           15 640  6800    8000            14 927  40 740   53 510
 Israel                                                                         8557    11 280   7550     5860
 Japan                                                  1800    1000                    128 880
 Jordan                                                 5000    4500                    103 736  40 382
 Korea Rep.   711     1426     1601             2759    726     337             24 522  28 224   28 615
 Kuwait       4                                 4
 Oman                                                   350     240                     830      498      108
 Pakistan     982     530      324              90      2381    675             7929    8998     7460
 Philippines                   4800                     630     310                              80
 Saudi Arabia                                   55
 Sri Lanka            590      1690                                                              20
 Turkey       6480    1750     1837             1939    550     577             20 764  11 000   11 550
 United Arab                                            34


 Austria      129     201      156     150                                      839     798      992      993
 Czecho-      20      130      44               187                             3370    4812     4892
 Denmark      1581             2578    2334     206             110     108     656              847      1123
 Finland      55                                74                              407
 Greece       2873                              2837                            6493
 Hungary      30 599  17 325   11 301  10 190   2711    1584    1598    3130    66 624  77 361   66 848   44 606
 Iceland      2       2        2                                                3       3        2
 Italy        23 147  24 231   18 591           8997    6068    5524            87 204  149 558  144 956
 Malta                                                  350                             250
 Norway                                                                         196     205      202      212
 Poland                                         530     707     1062    1038    6730    5099     12 246   13 549
 Portugal     301     509      643              109     144     227             854     818      880
 Sweden       3020                                      74      60                      1029     1264
 Switzerland  800     850      800
a   From: FAO (1984).
3.2.2.  Distribution in food

    Exposure of food materials to organophosphorus pesticides 
occurs chiefly at the crop-growing stage.  The scale and frequency 
of application varies enormously.  Thus, one or 2 applications may 
be adequate for pest control in temperate climates, while as many 
as 50 applications in one peach-growing season have been reported 
for a hot and humid region (Wicker et al., 1979).  The amount 
remaining on the crop at harvest depends chiefly on the interval 
between application and harvest and on the effects of rainfall, 
which can wash the active agent off and also provide a milieu for 
hydrolysis.  Thus, under exceedingly hot and dry conditions, very 
high residues of paraoxon were found on citrus plants that had been 
sprayed with parathion, 28 days previously: these levels accounted 
for the poisoning of several orange pickers, who were working in 
the grove at this time, after what is normally an acceptable safe 
interval from the time of spraying (Spear et al., 1977).  It seems 
that both excessive photo-oxidative formation of paraoxon and 
absence of hydrolysis or wash-off accounted for the toxic level of 
paraoxon.  Post-harvest levels of these organophosphorus pesticides 
in food appear to decline steadily: this loss is thought to be 
principally due to hydrolysis. Dichlorvos, malathion, or 
pirimiphos-methyl may be applied to stored grain for the control of 
some pests. 

    For each of the organophosphorus pesticides covered by the 
Joint FAO/WHO Meetings, considerable detail is available on the 
rate of decline of residues on a wide variety of crops, under 
different climatic conditions. 

3.3  Bioaccumulation and Degradation in the Environment

    While storage in the fat of an organism or animal may reduce 
the rate of clearance from that individual, it is unlikely that 
significant amounts of an organophosphorus pesticide stored in one 
organism could survive the hydrolytic processes of consumption and 
digestion to be stored successively by higher members of the food-
chain.  Direct poisoning of consumers of sprayed food or pest-
contaminated carcasses can occur, of course. 

    Degradation in the environment involves both hydrolysis and 
oxidation to mono- or di-substituted phosphoric or phosphonic acids 
or their thio analogues.  There is no evidence that these products 
are toxic to any significant extent.  If aerial oxidation of a 
phosphorothioate precedes hydrolysis, then the product will be a 
toxic anticholinesterase, so that hazard due to exposure may 
increase for a few days in a dry atmosphere after spraying (section 
2.1).  Occasionally, other reactions that can be regarded as 
chemical degradation yield a more toxic product.  Thus, leptophos 
(phosphonothioic acid, phenyl-,  O -(4-bromo-2,5-dichloro-phenyl) 
 O -methyl ester) is converted to its desbromo analogue in sunlight, 
and the product is considerably more active than the parent in 
causing delayed neuropathy (Johnson, 1975b; Sanborn et al., 1977).  
Further degradation of the acids to inorganic phosphate is not well 
documented, but bacterial cleavage of the carbon-phosphorus bond of 
a phosphonate has been reported (Daughton et al., 1979).  Whatever 

the precise means of degradation, it is clear that residues of most 
organophosphorus pesticides are rapidly lost from food crops and 
are usually barely detectable 4 weeks after application, though the 
exact rate of loss depends on the weather conditions.  For a few 
organophosphorus pesticides, such as leptophos and fenamiphos, the 
residual life is longer (El-Sebae, personal communication, 1985).  
Fenamiphos is claimed by its manufacturers to have a residual 
activity in soil of "several months" (Bayer, 1971). 

3.4  Exposure Levels 

3.4.1  Exposure of the general population

    Exposure of the general population may occur through the 
consumption of foodstuffs treated incorrectly with pesticides or 
harvested prematurely before residues have declined to acceptable 
levels, from contact with treated areas, or from domestic use. 

    Exposure of limited populations during disease vector control
is considered below.  Significant exposure of the general
population should be unlikely, since the use of these compounds
for crop protection under "good agriculture practice" does not
leave residues that are considered harmful in food.  At annual
meetings of the FAO Panel of Experts on Pesticide Residues in Food
and the Environment and the WHO Expert Group on Pesticide
Residues, data accumulated on new and older compounds over the
years are reviewed, and maximum residue limits (MRLs) in various
foods and acceptable daily intakes (ADIs) for the individual
compounds established.  The ADIs for the compounds discussed in
this review are given in Annex II.

3.4.2  Occupational exposure

    Exposure of factory workers during the undisturbed synthesis of 
pesticides is probably negligible, since the processes are carried 
out in closed vessels.  However, the formulation and dispensing of 
formulated pesticides may cause considerable contamination of 
workers.  The whole range of workers associated with pesticide-
treatment of crops or premises is also liable to exposure as are 
both workers and segments of the population during disease vector 
control procedures. 

    Exposure may be via the inhalation, dermal, or oral route. 
Dermal contact is the most important route of exposure for 
pesticide workers.  Durham & Wolfe (1962) described and evaluated 
procedures for the use of air samples, pads attached to exposed 
body surfaces, and washes, in the direct measurement of the dermal 
and respiratory exposure of workers to pesticides.  Good methods 
are not available for measuring oral exposure.  The extent of 
exposure depends on disciplined hygiene among workers.  Provided 
smoking, eating, and drinking in the work area are forbidden, and 
these activities are only engaged in after workers have washed 
thoroughly, oral intake should be negligible.  Exposure by other 
routes depends on the amount of protective clothing worn, and, on 
the physical state of the pesticide.  The majority of 
organophosphorus pesticides are liquids having different vapour 

pressures at room temperature (i.e., dichlorvos is much more 
volatile than malathion); thus, hazard due to inhalation of vapour 
varies from compound to compound.  The vapour pressure of the 
active agent is reduced on dilution with solvent, emulsifier, etc., 
so that the inhalation hazard is reduced, but these additives may 
facilitate adsorption of spilled material through the skin.  The 
likelihood of acute poisoning occurring among process workers seems 
greatest when dealing with liquid formulations.  It was impossible 
to judge the comparative contributions via the dermal and 
respiratory routes in the case of poisoning with demeton- S -methyl 
reported by Vale & Scott (1974), but it was noted that the area 
where intoxication occurred was an unventilated cubicle.  The 
routine use of gas masks or bottled air respirators may be 
necessary, when concentrated liquid pesticides are dispensed.  In 
studies on several powder-formulated pesticides, Wolfe et al. 
(1978) showed that potential dermal exposure markedly exceeded 
respiratory exposure; thus, the mean exposure to parathion for the 
most contaminated group of workers in a formulation plant was 184 
mg/h of work activity for dermal contamination and 0.03 mg/h for 
respiratory exposure, the highest values being 33.5 and 33.8 mg/h, 
respectively, for one individual.  The actual uptake as a result of 
such exposures is harder to quantify and may vary according to the 
mode of formulation of the pesticide as well as to the 
lipophilicity and volatility of the compound and the area of 
exposed skin.  Using the calculations of Durham & Wolfe (1962), the 
highest exposure noted above would have represented 25% of the 
toxic dose, had it all been absorbed.  However, these authors 
calculated that even with contamination by liquid parathion 
formulations (which presumably enter more easily through contact 
with the skin), the amount absorbed by orchard spraymen was only a 
mean 1.23% (0.40 - 1.95% range) of the measured potential dermal 
exposure (Durham et al., 1972).  The mean dermal and respiratory 
exposures of the spraymen were 19 and 0.02 mg/h, respectively, 
which was markedly lower than those in the formulating plant.  In 
view of the inefficiency of absorption, it is perhaps less 
surprising that ChE changes were negligible, though total urinary 
4-nitrophenol excretion was significant, when a volunteer was 
totally covered with 2% parathion dust and enclosed in a rubber 
suit for 7 h, spent alternatively in the sun and shade (Hayes et 
al., 1964). 

    Similarly, a 2-h exposure to 48% parathion emulsifiable 
concentrate swabbed on the right hand and forearm of a volunteer to 
the point of run-off did not cause any change in erythrocyte- or 
plasma-ChEs and an average of 10 µg 4-nitrophenol/h was excreted 
during the following 24 h.  Hayes (1971) stated that absorption of 
parathion was tolerated without illness and with little or no 
reduction in ChE activity, as long as the concentration of 
4-nitrophenol in the urine did not rise above 60 - 80 µg/h (2 ppm), 
assuming an average urine excretion of 30 - 40 ml/h. 

    Studies on orchard spray workers (Wolfe et al., 1967) showed 
that, as in the formulation plant, the potential exposure of a 
worker without special protective clothing was largely dermal, for 
instance, 19.4 mg parathion/h by dermal exposure and 0.02 mg/h 
respiratory.  This is about 3 times less than the mean exposure of 

some formulator/baggers (see above).  However, the respiratory 
exposure was increased 4-fold, when applying dusts compared with 
dilute spray, and 10-fold, when using aerosols of concentrated 
pesticide (not necessarily organophosphates).  Thus, in the last 
case, the respiratory route could be highly important when the 
efficiency of absorption is allowed for. 

    The droplet size in pesticide sprays is influenced by the spray 
machinery and a recent study compared potential dermal exposure 
during mixing and loading with that during spraying with various 
machines.  Knapsack spraying seemed to cause much greater dermal 
exposure in operators than electrostatic spraying (British 
Agrochemical Association, 1983). 

    Significant exposure of workers may occur when they enter a 
previously sprayed crop area for the purposes of further 
cultivation or hand-harvesting.  The re-entry concept was first 
discussed by Milby et al. (1964) in relation to the prevention of 
illness.  The extent of exposure depends on many factors, including 
the physical properties of the pesticide and its biodegradability, 
the crop, the nature of the proposed worker operation, and, also, 
on the local weather; thus, marked regional differences may occur.  
Procedures for determining foliar residues and their dissipation 
rates were described by Gunther et al. (1973, 1974), and the topic 
was further reviewed by Knaak (1980). Kahn (1979) provided an 
outline guide to the procedures and factors to be considered when 
performing field studies to establish safe re-entry intervals in 
relation to organophosphorus pesticides.  One such study was 
described by Guthrie et al. (1974).  Kahn (1979) cited the US EPA 
(1975) in its Registration Procedures as requiring "data necessary 
to determine required intervals between pesticide application and 
safe re-entry". Re-entry periods appropriate to local conditions 
for some pesticides and crops have been reported by Knaak (1980) 
and by Kaloyanova-Simeonova & Izmirova-Mosheva (1983). 

    The situation for workers entering fields that have been 
sprayed with some organophosphorus esters differs from that of 
workers exposed to dieldrin, for example.  In the case of the 
former, the oxidation products generated by the action of light and 
air may be far more toxic for man than the applied pesticide 
(section 2.1), so that the residues on the crops may be more 
hazardous for a few days after application than at the time of 
application.  Degradation is fairly rapid, but clearly a balance of 
effects between activation and degradation must be taken into 
account, initially. 

    A "Standard Protocol for Field Surveys of Exposure to
Pesticides" has been published by the World Health Organization
(WHO, 1982).


4.1  Uptake

    Most organophosphorus pesticides are not ionized and are very 
lipophilic.  Thus, inhaled or swallowed material will be easily 
taken up. 

4.1.1  Dermal uptake

    Many accidental acute poisonings have occurred following 
spillage of pesticide on skin and clothing.  The extent of uptake 
will depend on persistence time (related to volatility, clothing, 
coverage, and thoroughness of washing after exposure), and also on 
the presence of solvents and emulsifiers that may facilitate 
uptake.  However, the evidence concerning parathion, quoted in 
section 3.4.2, suggests that dermal absorption is not an efficient 
process, under normal working conditions.  Experimental 
determinations of dermal toxicity depend on the conditions 
employed, particularly on whether the treated skin is covered or 
not, and on how long the application is left before cleansing. 
These are frequently not stated in toxicological reports.  With 
this limitation in mind, the comparison can be made for the 
toxicity of omethoate in rats by 2 routes: the dermal LD50 is 860 - 
1020 mg/kg body weight and the oral LD50 is 25 - 28 mg/kg body 
weight (FAO/WHO, 1979b).  In contrast, uptake through the skin can 
be very efficient for more lipophilic agents and, since they avoid 
the first-pass metabolic disposal in the liver, agents such as DEF 
and EPN may be at least as toxic by the dermal route as by the oral 
route in laboratory tests. 

4.1.2  Gastrointestinal tract

    In rats, the uptake of most of the organophosphorus pesticides 
reviewed seems to be rapid and efficient under test conditions 
usually involving a dose well below the LD50. 

    However, the question that does not appear to have been 
answered is whether this is true with large doses of low-toxicity 
compounds.  Thus, the LD50 of bromophos, for rats, is > 3 g/kg 
body weight (FAO/WHO, 1973b), but it is not clear whether this low 
toxicity is in part a reflection of failure to absorb the majority 
of the dose above some unknown threshold.  In absorption studies, 
using radiolabelled bromophos at a dose of 10 mg/kg body weight, 
approximately 96% of the radiolabel was absorbed and excreted in 
the urine within 24 h of oral dosing. There is evidence of 
comparatively inefficient absorption in hens administered large 
doses of very insoluble organophosphorus pesticides with a high 

relative molecular mass, such as haloxon [phosphoric acid, 3-
chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl bis-(2-chloroethyl) 


or leptophos [phosphonothioic acid, phenyl-,  O -(4-bromo-2,5-
dichlorophenyl)  O -methyl ester]:


Thus, divided doses may exert a greater toxic effect than the same 
amount given as a single large dose (section 6.1.2). 

    The question of the bioavailability of preparations given by 
the oral route needs to be considered.  It must be taken into 
account when discussing the results obtained for LD50s, and it is 
certainly important when considering the toxicity of pesticides 
residues.  From a chemical point of view, these residues can be 
described as parent compounds, free metabolites, and their 
conjugates (Kaufman, 1976).  The bioavailability of these 
fractions and, thus, their toxic potential are not the same 
(Dorough, 1976; Marshall & Dorough, 1977).  In general, bound 
residues appear to have a lower bioavailability and lower toxicity.  
This was discussed by Rico & Burgat-Sacaze (1984), and demonstrated 
for some pesticides residues by Marshall & Dorough (1977). 

4.1.3  Inhalation

    Total urinary output of 4-nitrophenol was compared in workers 
spraying parathion, who either breathed a pure air supply but did 
not wear protective clothing, or who wore total protective 
clothing, but did not have any respiratory protection (Durham et 
al., 1972).  Output derived from the respiratory source compared 
with that derived from the dermal source was 1.2% in one test and 
12% in another.  Since the total exposures by the dermal and 
respiratory routes were in the proportion of 1000:1, and the 
efficiency of dermal absorption was 1 - 2%, it follows that the 
efficiency of absorption by the respiratory route was higher than 
20% and could well have been complete. 

 4.2  Distribution and Storage 

    The intrinsically reactive chemical nature of organophosphorus 
pesticides means that any that enter the body are immediately 
liable to a number of biotransformations and reactions with tissue 
constituents (particularly tissue proteins carrying esterase active 
sites), so that the tracing of radiolabelled material alone does 
not give any clue to the distribution of the unchanged parent 
compound.  It is possible to determine the rate of disposal of 
metabolites and thereby to estimate an approximate half-life of 
pesticide in the body.  Such numbers may be helpful in estimating 
safe intervals between successive low exposures, under working 
conditions.  However, although the half-life of organophosphorus 
pesticides and their inhibitory metabolites  in vivo is 
comparatively short, at least one case of poisoning demonstrated 
that significant amounts remained in the body for several weeks 
after an acute crisis.  Ecobichon et al. (1977) reported a case of 
poisoning by fenitrothion.  After an effective treatment period 
with atropine and an oxime reactivator, leading to 2 days without 
symptoms or any therapy, symptoms of nausea and diarrhoea recurred 
associated with a decline in the previously restored blood-ChE 
levels.  These symptoms were controlled by further administration 
of oxime, which led to a prompt restoration of the enzyme to a 
near-normal level. Further recurrence of symptoms was reported, at 
intervals, especially associated with periods of mobilization of 
adipose tissue. The conclusion is that the treatment was reversing 
the recent inhibition of AChE by a compound that had been stored in 
the body and was entering the circulation over a period of many 

4.2.1  Experimental animal studies on distribution and storage

    In view of the inherent instability of organophosphorus 
insecticides, storage in human tissue is not anticipated to be 
prolonged (unlike the situation for DDT); population studies, 
including analyses of cadavers, do not seem to have been carried 
out and would be a pointless exercise.  Experimental animal studies 
have shown that most of a radiolabelled dose is rapidly excreted in 
expired air, urine, and faeces.  Thus, it was reported that from 67 
to 100% of the administered radioactivity was recovered within 1 
week in the combined urine and faeces of cows, rats, and a goat, 
given various doses of 32 P-dichlorvos; no organosoluble 
radioactivity, which might include unchanged dichlorvos, was 
detected after the first 2 h (Blair et al., 1975), though 14 C in 
alkyl groups may enter the general metabolic pool and be 
incorporated into tissues.  Also, phosphorylated proteins are 
presumably replaced only by resynthesis and this is a comparatively 
slow process with enzymes, such as erythrocyte- and brain-AChE, 
typically returning to pre-exposure levels over a period of a few 
weeks after irreversible phosphorylation. 

    In a case of human poisoning by dichlorofenthion, steadily 
decreasing concentrations of the pesticide were found in serial fat 
biopsy samples up to 48 days after intoxication:  the decline 
matched a return of blood-ChE levels towards normal, and recovery 
of health.  Indirect evidence for the short-term storage of 

significant amounts of lipophilic organophosphorus compounds was 
the return of cholinergic poisoning signs a day or two after 
discontinuing oxime therapy in a woman who had been accidentally 
poisoned with fenitrothion (Ecobichon et al., 1977). Reinstatement 
of therapy led to rapid amelioration of signs and the cycle was 
repeated at intervals up to the 15th day after intoxication, after 
which her health improved slowly. 

4.3  Biotransformation

    Alternative metabolic pathways, often available in animals and 
man, are listed below, with examples. Most general studies of 
pathways have been made on phosphates and their thioate analogues.  
Although the ultimate fate of phosphonate pesticides has been 
determined, the pathways are usually presumed on the basis of 
phosphate studies, which indicate that cleavage of the phosphoric-
carbon bond is limited in mammalian systems.  A summary is given 
below; further details can be found in Dauterman (1971), Eto 
(1974), CEC (1977), and in the annual reports of the Joint FAO/WHO 
Meetings on Pesticide Residues in Food (Annex II). 
Biotransformation reactions can be divided into three distinct 
classes.  The former are reactions involving (a) mixed-function 
oxidases; (b) hydrolases; and (c) transferases.  There is also a 
miscellaneous group of unrelated reactions.  Binding of 
organophosphorus insecticide oxons to tissue is also a significant 
biotransformation reaction. 

4.3.1  Mixed-function oxidases (MFOs)

    Many apparently unrelated substrates can be oxidized by mixed-
function oxidase (MFO) systems associated typically with liver 
endoplasmic reticulum, but present also in some other tissues such 
as intestine, lung, and kidney.  Within the liver, there appears to 
be a family of MFOs, possibly with some enzymes in common, but 
utilizing slightly different cytochromes of which cytochrome P-450 
is the best known.  The MFO activity in the liver can vary greatly 
according to the nutritional and hormonal state of the animal and 
also according to stimuli arising from the ingestion of some 
foreign compounds (section 6.3).  Oxidative desulfuration

    The reaction (Fig. 1) is essentially the activation of the 
precursor phosphorothioate to the directly inhibitory phosphate 
ester, which is responsible for the inhibition of AChE and for 
subsequent toxic effects.  There is no evidence of inhibition of 
AChE by phosphorothioates occurring under normal situations, 
without prior conversion to the phosphate; reports of the 
inhibitory power of technical grades of phosphorothioates  in vitro 
are meaningless, since the activity is almost certainly caused by 
traces of the oxon, the activity of which is several orders 

FIGURE 1  Oxidative  N -dealkylation

    This reaction may be associated with the metabolic activation 
of a non-inhibitory precursor, such as schradan, or with 
transformation of one inhibitor to another (Fig. 2). 

FIGURE 2  Oxidative  O -dealkylation

    The conversion of triesters to diester is a detoxication 
process and was once considered to be mediated only by hydrolytic 
enzymes (phosphoryl phosphatases or A-esterases). However, a 
reaction requiring liver microsomes, NADPH, and oxygen (the typical 
MFO system) deethylates chlorofenvinphos with the production of 
acetaldehyde, probably as shown in Fig. 3.  It seems that various 
phosphates, but not phosphorothioates, are metabolized by this 
route in mammals. 

FIGURE 3  Oxidative de-arylation

    Liver MFOs from rat or rabbit can cleave the acid-anhydride 
bond coupling phosphorus to the phenolic group in parathion and 
analogues (Nakatsugawa et al., 1968), and the same system may also 
be responsible for the cleavage of diazinon (Yang et al., 1971).  
In contrast to  O -dealkylation noted above, this reaction appears 
to deal only with phosphorothioates and not phosphates.  Thioether oxidation

    Oxidation of sulfur in the phosphorus-sulfur-carbon moiety of 
demeton-S or or dimethoate and omethoate has not been reported, but 
oxidation is known of carbon-sulfur-carbon moieties with the 
formation of sulfoxides and sulfones that are more active AChE 
inhibitors than the parent compound and remain in circulation for a 
comparatively long time (Fig. 4). 

FIGURE 4  Side-chain oxidation

    Stepwise oxidation of simple alkyl groups to hydroxy-, oxo-, or 
carboxy-derivatives is a well-known process in the metabolism of 
many compounds, apart from the organophosphorus compounds.  The 
conversion of fenitrothion to the water-soluble, 3-carboxy 
derivative (Fig. 5) can account for the comparatively low mammalian 
toxicity of this pesticide compared with that of the homologous 
methyl parathion (rat oral LD50s of about 600 - 800 and 10 - 25 
mg/kg body weight, respectively). 


4.3.2  Hydrolases

    Hydrolysis of the acid anhydride type ester bond of the leaving 
group in pesticidal triesters is well known.  The monobasic 
diesters and their derivatives are the major urinary metabolites of 
organophosphorus insecticides (Fig. 6).  The enzymes commonly known 
as A-esterases or phosphoryl phosphatases are widespread in 
mammalian tissues, such as liver, plasma, intestine, etc., though 
they are less abundant in many birds and may not be present in some 
insects (Brealey et al., 1980).  These enzymes are sometimes 
referred to as DFPase or paraoxonase according to the substrate 
used, but it does not mean that the enzymes are specific only for a 
given organophosphorus compound.  Although plasma contains enzymes 
that can distinguish between closely related structures such as 
paraoxon and 4-nitrophenyl, ethyl, or propylphosphonate, the 
enzymes are not totally specific (Becker & Barbaro, 1964); the same 
is probably true of A-esterase in other tissues. 


    Hydrolysis of carboxylic acid ester bonds and carboxyl-amide 
bonds in organophosphorus insecticides may be catalysed by 
carboxylesterases (or B-esterases), which again occur widely in 
mammalian tissues.  Malathion, which contains 2 carboxylic ester 
bonds, is the best-known organophosphorus pesticide that is 

hydrolysed in this way (Fig. 7).  The importance of this metabolic 
route is shown by the fact that the rat oral LD50 for pure 
malathion can be reduced from 10 000 to 100 mg/kg body weight, when 
the tissue carboxyesterases are inhibited: this profound 
potentiation is discussed further in section 5.3. 

    The hydrolysis of carboxylamide bonds such as in dimethoate is 
catalysed by a liver enzyme (Chen & Dauterman, 1971) (Fig. 7).  
Although apparently distinct from liver carboxyesterase, it too is 
inhibited by its oxygen analogue (omethoate) and also by other 
amide-containing phosphates such as dicrotophos. 


4.3.3  Transferases

    The only transferase reaction that is known to deal with the 
intact pesticidal organophosphorus triesters involves glutathione, 
which is a required substrate for a number of transferase enzymes 
present in liver and some other tissues. The enzymes have limited 
but overlapping specificity so that the glutathione transferase 
responsible for demethylating methyl paraoxon is distinct from that 
which conjugates the 4-nitrophenol group in parathion.  Activity in 
the liver is greatest with methyl esters, but no evidence has been 
found of methyl phosphonates undergoing this reaction (Dauterman, 
1971).  Transferases handling primary metabolites

    Reactions involving the conjugation of carboxylic acids, 
alcohols, phenols, and amino, imino, and sulfydryl groups are well-
known and applicable to compounds carrying such groups, formed 
after the oxidation, hydrolysis, etc. of an organophosphorus 
pesticide.  Such conjugation reactions aid in the elimination of 
primary degradation products, which are usually devoid of 
anticholinesterase activity, though they may cause other toxic 
effects if they accumulate in the body. 

4.3.4  Tissue binding

    It is well-known that active metabolites of most 
organophosphorus insecticides react covalently to some extent with 
tissue esterases other than AChE. Since few of these esterases 

appear vital to health (section 6.2.4), the binding reaction may be 
considered a detoxification process.  Although the catalytic 
activity of these esterases is high, the actual quantity of such 
sites is comparatively small.  Crude measurements using 32 P-
labelled diisopropyl phosphorofluoridate (an agent reacting with 
most organophosphorus-sensitive esterases) suggest that 100 - 150 
µg bind per kg body weight of an adult hen injected with about the 
LD50 dose (Johnson, M.K., personal communication, 1985).  Binding 
was principally in liver and muscle.  The quantity bound would not 
be expected to be much greater whatever the LD50 of an administered 
organophosphorus insecticide.  Thus, it is a significant proportion 
of the total dose only for a very toxic compound such as paraoxon 
(Lauwerys & Murphy, 1969) but not for compounds with much higher 
LD50s.  However, the number of binding sites may, in some cases, be 
very significant compared with the quantity of circulating 
anticholinesterase oxon that has avoided other metabolic disposal 
processes.  Molecules of oxon bound to these non-vial sites are 
prevented from attacking the vital sites such as AChE or NTE 
(section 6.1).  Binding sites can therefore be considered an 
important second line of defence against intoxication. 

    The specific problem of tissue binding that leads to 
potentiation of the toxicity of malathion and other pesticides 
containing carboxylester bonds is discussed in section 6.2.4. 

4.4  Elimination

    There is no evidence of prolonged storage of organophosphorus 
compounds in the body, but the process of elimination can be 
subdivided roughly according to the speed of the reactions 
involved.  Most organophosphorus pesticides are degraded quickly by 
the metabolic reactions listed in section 4.3, and the elimination 
of the products, mostly in the urine with lesser amounts in faeces 
and expired air, is not delayed, so that rates of excretion usually 
reach a peak within 2 days and decline quite rapidly. That they do 
not almost immediately fall to zero is due to storage in fat and 
covalent binding. As indicated in section 4.2, the former process 
preserves toxic material, which is slowly released into the 
circulation and which is active and is metabolized in the same way 
as the bulk of the dose received.  Covalent binding involves 
phosphorylation of proteins, probably esterases having active 
sites, including serine, which are mechanistically related to AChE.  
The consequences of such phosphorylation depend on the esterase 
involved, but many seem to be of only minor importance to the 
continuing health of animals, and temporary inhibition may not be 
expressed in physiological defects.  The special case of neuropathy 
target esterase, which is phosphorylated only by agents capable of 
causing delayed neuropathy, is considered later (section 

4.5  Mode of Action

4.5.1  Inhibition of esterases

    The primary biochemical effect associated with toxicity caused 
by organophosphorus pesticides is inhibition of AChE. The normal 
function of AChE is to terminate neurotransmission due to ACh that 

has been liberated at cholinergic nerve endings in response to 
nervous stimuli.  Loss of AChE activity may lead to a range of 
effects resulting from excessive nervous stimulation and 
culminating in respiratory failure and death (section 6.1).  The 
chemistry of inhibition of AChE and of many other esterases (e.g., 
NTE and liver carboxyesterases, which are discussed elsewhere) by 
these chemicals is similar and is given in schematic form in Fig. 
8.  Following the formation of a Michaelis complex (reaction 1), a 
specific serine residue in the protein is phosphorylated with loss 
of the leaving group X (reaction 2).  Two further reactions are 
possible: reaction 3 (reactivation) may occur spontaneously at a 
rate that is dependent on the nature of the attached group and on 
the protein and is also dependent on the influence of pH and of 
added nucleophilic reagents, such as oximes, which may catalyse 
reactivation.  Reaction 4 ("aging") involves cleavage of an R-O-P-
bond with the loss of R and the formation of a charged mono-
substituted phosphoric acid residue still attached to protein.  The 
reaction is called "aging" because it is time-dependent, and the 
product is no longer responsive to nucleophilic reactivating agents 
such as some oximes. Since therapy of organophosphorus compound 
poisoning is, in part, dependent on the reactivating power of 
oximes (sections 6, 7), understanding of the "aging" reaction is 
important. PseudoChE, which is present in blood-plasma and nervous 
tissue but has no known physiological function, is inhibited by 
organophosphorus compounds in a similar way to AChE, but the 
specificity of the 2 enzymes is different.  Though no toxic effect 
arises as a result of inhibition of pseudoChE, measures of its 
inhibition can be made for monitoring purposes (section 

4.5.2  Possible alkylation of biological macromolecules

    It has been shown, under laboratory conditions, that some 
organophosphates could react with and alkylate the reagent 
4-nitrobenzylpyridine (Preussmann et al., 1969).  The study was 
interpreted to imply that the  in vivo alkylating potential of some 
pesticides was similar to that of the known mutagens dimethyl 
sulfate and methyl methanesulfonate.  Furthermore, Löfroth et al., 
(1969) derived a substrate constant (a logarithmic measure of 
alkylating ability) of 0.75 for dichlorvos, which is intermediate 
between those known for methyl and ethyl methanesulfonates.  
Concern over the possible mutagenic and carcinogenic potential of 
organophosphorus compounds on the basis of the above data was 
misplaced, since alternative reactions were not considered.  
Compared with the carbon atom of the alkyl group, the phosphorus 
atom is markedly more electron-deficient and susceptible to attack 
by nucleophiles.  Analysis by Bedford & Robinson (1972) of the data 
of Löfroth et al. (1969) revealed that the proposed rates of 
alkylation by hard nucleophiles were probably combined rates of 
phosphorylation and alkylation, and that phosphorylation was the 
totally dominant reaction in the case of the hydroxide ion.  The 
comparison with known mutagens was therefore inappropriate.  Two 
factors detract further from the toxicological significance of the 
alkylation studies.  The first is that mammalian tissues (plasma, 
liver, etc.) contain active enzymes that catalyse the 
phosphorylation of water by the organophosphorus esters.  Viewed 
inversely, these enzymes (often called A-esterases) catalyse the 
hydrolysis of the organophosphorus esters, thereby rapidly reducing 

circulating levels of hazardous material.  Secondly, the 
comparative rate of reaction of most of these pesticides with AChE 
is many orders greater than their rate of alkylation of the typical 
nucleophile 4-nitrobenzylpyridine: for dichlorvos, the ratio of 
rates was 1 x 107  in favour of the inhibitory phosphorylation of 
AChE (Aldridge & Johnson, 1977).  It follows that, at low exposure 
levels,  in vivo phosphorylation of AChE and other esterases will 
be the dominant reaction with negligible uncatalysed alkylation of 
genetic material.  Indeed, no such alkylation has been detected in 
sensitive  in vivo studies designed to check this point (Wooder et 
al., 1977).  Some catalysed alkylations of glutathione by 
organophosphorus compounds are known to occur  in vivo (section 4), 
but these are essentially detoxification reactions.  The topic of 
alkylation and the possible mutagenic or carcinogenic consequences 
is discussed further in section 6.2. 



5.1  Aquatic Organisms

    Organophosphorus insecticides are not very stable in aqueous 
media.  However, accidental leaching may occur from treated areas 
into rivers and lakes where they may exert toxic effects on aquatic 
organisms before degradation is complete. In clean water in the 
laboratory, toxic effects were seen in several aquatic organisms 
when they were exposed to concentrations of organophosphorus 
insecticides ranging from 0.01 to 1 mg/litre for 48 h (Nishiuchi, 
1981).  However, lethal concentrations derived from 48-h exposures 
in clear laboratory water may be artificially low compared with the 
concentrations that would be effective in true environmental 

    One pesticide (phenthoate) appeared to be more toxic for 
aquatic insects ("median tolerable limit" = 9 - 75 µg/kg) 
(Nishiuchi, 1981) than for one species of fresh-water fish exposed 
under apparently similar conditions (20% mortality caused by 263 
µg/kg) (Jash & Bhattacharya, 1982). 

    Accidental release of pesticides in lakes, rivers, and bays 
sometimes caused massive death of fish and many of the compounds 
were strongly toxic for small aquatic organisms such as  Daphnia, as 
shown in Table 3. 

Table 3.  Acute toxicity of organophosphorus pesticides for some aquatic organisms
Pesticide                    TLMs for organisms at indicated time (mg/litre)             Reference
                  Carp          Goldfish      Killifish     Guppy          Water flea
                  ( Cyprinus     (Carassius   (Fundulus     (Lebistes      (Daphnia
                   carpio        auratus)     sp)            reticulatus   pulex
                  Linné)                                    Peters)        Leydig)                              
                  48 h          48 h          48 h          48 h           3 h
Acephate          > 40          -             > 40          -               > 40         Nishiuchi (1974)
Calvinphos        > 40          -             > 40          -              0.0042        Nishiuchi (1974)
Chlorfenvinphos   0.27          0.34          0.23          0.12           0.011         Yoshida & 
                                                                                         Nishiuchi (1972);
                                                                                         Nishiuchi (1974)
Chlorpyrifos      0.13          0.20          0.47          0.74           0.0050        Yoshida & 
                                              emulsifiable                               Nishiuchi (1972); 
                                              concentrate)                               Nishiuchi (1974)
Chlorpyrifos      2.1           -             3.4           -              0.017         Yoshida & 
-methyl                                                                                  Nishiuchi (1976)

Cyanofenphos      1.2           1.3           6.3           15             0.0085        Yoshida & 
                                                                                         Nishiuchi (1972);
                                                                                         Nishiuchi (1974)
Cyanophos         15            10 ~ 40       28            18             0.34          Yoshida & 
                                                            (wettable                    Nishiuchi (1972);   
                                                            powder)                      Nishiuchi (1974)
Dialifos          1.3           -             0.80          -              0.027         Yoshida & 
                                                                                         Nishiuchi (1976)
Dichlofenthion    5.1           10 ~ 40       1.4           10             0.005         Yoshida & 
                                              (emulsifiable (dust                        Nishiuchi (1972); 
                                              concentrate)  formulation)                 Nishiuchi (1974)
Diazinon          3.2           5.1           5.3           4.1            0.08          Yoshida & 
                                                                                         Nishiuchi (1972);
                                                                                         Nishiuchi (1974)

Dichlorvos        > 40          10 ~ 40       18            -              2.8           Yoshida & 
                                              (emulsifiable                              Nishiuchi (1972)
Dimethoate        > 40          > 40          > 40        -                10 ~ 40       Yoshida & 
                                                                                         Nishiuchi (1972)

Table 3.  (contd.)
Pesticide                    TLMs for organisms at indicated time (mg/litre)             Reference
                  Carp          Goldfish      Killifish     Guppy          Water flea
                  ( Cyprinus     (Carassius   (Fundulus     (Lebistes      (Daphnia
                   carpio        auratus)     sp)            reticulatus   pulex
                  Linné)                                    Peters)        Leydig)                              
                  48 h          48 h          48 h          48 h           3 h
Dimethylvinphos   5.6           -             1.5           -              0.010         Yoshida & 
                                                                                         Nishiuchi (1976)
Dioxathion        10 ~ 40       10 ~ 40       1.4           -              0.007         Yoshida & 
                                              (emulsifiable                              Nishiuchi (1972)
Disulfoton        8.7           10 ~ 40       21            0.37           0.07          Yoshida & 
                                                                                         Nishiuchi (1972); 
                                                                                         Nishiuchi (1974)
Edifenphos        2.5           1.8           1.8           -              0.27          Yoshida & 
                                (emulsifiable (emulsifiable                              Nishiuchi (1972)
                                concentrate)  concentrate)

EPN               0.20          0.32          0.50          0.085          0.0017        Yoshida & 
                                                                                         Nishiuchi (1972);     
                                                                                         Nishiuchi (1974)
Ethion            1.2           1.1           5.5           -              0.005         Yoshida & 
                                                                                         Nishiuchi (1972)
Fenitrothion      8.2           3.4           7.0           0.75           0.050         Yoshida & 
                                                                                         Nishiuchi (1972);     
                                                                                         Nishiuchi (1974)
Fenthion          3.3           1.9           2.5           2.3            0.070         Yoshida & 
                                                                                         Nishiuchi (1972);
                                                                                         Nishiuchi (1974)
Formothion        15            10 ~ 40       10 ~ 40       -              5.8           Yoshida & 
                                                                                         Nishiuchi (1972)
IBP               10 ~ 40       12            7.2           -              2.3           Yoshida & 
                                (emulsifiable (emulsifiable                              Nishiuchi (1972)
                                concentrate)  concentrate)
Leptophos         > 40          10 ~ 40       8.5           -              0.002         Yoshida & 
                                              (emulsifiable                              Nishiuchi (1972)

Table 3.  (contd.)
Pesticide                    TLMs for organisms at indicated time (mg/litre)             Reference
                  Carp          Goldfish      Killifish     Guppy          Water flea
                  ( Cyprinus     (Carassius   (Fundulus     (Lebistes      (Daphnia
                   carpio        auratus)     sp)            reticulatus   pulex
                  Linné)                                    Peters)        Leydig)                              
                  48 h          48 h          48 h          48 h           3 h
Malathion         23            7.8           0.75          1.4            0.030         Yoshida & 
                                                                                         Nishiuchi (1972)
Menazon           > 40          > 40          > 40          100           10 ~ 40       Yoshida & 
                                                            (wettable                    Nishiuchi (1972);   
                                                            powder)                      Nishiuchi (1974)
Methidathion      2.5           2.3           0.034         0.22           0.007         Yoshida & 
                                              (emulsifiable                              Nishiuchi (1972); 
                                              concentrate)                               Nishiuchi (1974)
Naled             1.3           1.2           28            2.3            0.005         Yoshida & 
                                              (emulsifiable (emulsifiable                Nishiuchi (1972); 
                                              concentrate)  concentrate)                 Nishiuchi (1974)
Parathion         4.5           1.7           2.9           -              0.0050        Yoshida & 
                                                                                         Nishiuchi (1972)
Parathion-methyl  7.5           10 ~ 40       12            -              0.00050       Yoshida & 
                                                                                         Nishiuchi (1972)
Phenkapton        2.0           3.8           3.5           -              0.008         Yoshida & 
                                                                                         Nishiuchi (1972)
Phenthoate        2.5           2.4           0.17          0.20           0.008         Yoshida & 
                                                                                         Nishiuchi (1972); 
                                                                                         Nishiuchi (1974)
Phosalone         1.2           1.2           0.35          -              0.05          Yoshida & 
                                              (emulsifiable                              Nishiuchi (1972)
Phosmet           5.3           4.7           1.8           1.0            0.025         Yoshida & 
                                                                                         Nishiuchi (1972); 
                                                                                         Nishiuchi (1974)
Pirimiphos-methyl 1.8           -             3.0           -              0.018         Yoshida & 
                                                                                         Nishiuchi (1976)
Propaphos         4.8           -             4.1           -              0.0063        Yoshida & 
                                                                                         Nishiuchi (1976)

Table 3.  (contd.)
Pesticide                    TLMs for organisms at indicated time (mg/litre)             Reference
                  Carp          Goldfish      Killifish     Guppy          Water flea
                  ( Cyprinus     (Carassius   (Fundulus     (Lebistes      (Daphnia
                   carpio        auratus)     sp)            reticulatus   pulex
                  Linné)                                    Peters)        Leydig)                              
                  48 h          48 h          48 h          48 h           3 h
Propoxur          10 ~ 40       10 ~ 40       10 ~ 40       -              0.37          Yoshida & 
                                                                                         Nishiuchi (1972)
Prothiophos       9.5           -             10            -              0.13          Yoshida & 
                                                                                         Nishiuchi (1976)
Temivinphos       0.58          -             0.48          -              0.0080        Yoshida & 
                                                                                         Nishiuchi (1976)
TEPP              5.6           10 ~ 40       4.8           -              10 ~ 40       Yoshida & 
                  (liquid       (liquid       (liquid                      (liquid       Nishiuchi (1972)
                  formulation)  formulation)  formulation)                 formulation)
Tetrachlorvinphos 4.3           3.9           4.2           -              0.0035        Yoshida & 
                                              (wettable                                  Nishiuchi (1972)
Thiometon         7.5           10 ~ 40       10 ~ 40       -              5.5           Yoshida & 
                                                                                         Nishiuchi (1972)
Trichlorphon      28            10 ~ 40       25            12             0.005         Yoshida & 
                                                                                         Nishiuchi (1972); 
                                                                                         Nishiuchi (1974)
Vamidothion       > 40          > 40          > 40          -               > 40         Yoshida & 
                                                                                         Nishiuchi (1972)
 Note: Test methods are officially recognized methods based on the Notification of the Ministry of 
      Agriculture, Forestry and Fishery of Japan, as described in the separate papers.


    Insecticides are designed as lethal agents.  Although they may 
be designed to be less toxic for animals than for insects, all 
organophosphorus insecticides present a toxic hazard to some 
extent.  Values for the oral and dermal LD50s in rat, shown for 
different compounds in Annex III, range from less than 10 to more 
than 3000 mg/kg body weight. The dose-response line for 
organophosphorus insecticides is usually steeper than that for 
carbamates, though both kill by their anticholinesterase action.  
The reason for the difference lies in the faster rate of 
spontaneous reactivation of carbamylated AChE compared with 
phosphorylated AChE. 

    By the time the 1984 Joint FAO/WHO Meeting on Pesticide 
Residues (JMPR) had ended, the toxicology of 57 organophosphorus 
pesticides had been reviewed (Vettorazzi, 1984). Usually, the 
compounds had been reviewed several times as additional information 
became available.  The compounds, with the years of the JMPR 
review, and the acceptable daily intake (ADI) advised are listed 
Annex II.  It also lists the year of review by IARC.  Moreover, it 
gives the WHO recommended classification by acute toxic hazard 
(WHO, 1984a) and an indication on whether WHO/FAO issued a "Data 
Sheet on Chemical Pesticides" on this substance. 

    Details of the tests and of the results are recorded in the 
appropriate published evaluations from the FAO/WHO Joint Committee 
Meetings, which have been summarized and commented on by Vettorazzi 

    It should be realized that, while reports on toxicological 
tests may give some indication of the purity of the sample as 
percentage content of the major active ingredient, there is seldom 
any indication of the nature or quantity of the impurities or of 
whether the impurities may significantly influence toxicity.  It 
cannot be emphasized too strongly that measurements such as acute 
LD50s are not absolute values. 

    The LD50 values for one typical compound, fenitrothion, in 
various species when administered by various routes are listed in 
Table 4 (FAO/WHO, 1970b, 1975b).  From this Table, it is clear that 
there are marked differences in the LD50 depending on species and 
route of administration.  Variability in LD50 values for the same 
route and species is often considered to be due to the vehicule in 
which the pesticide is applied, which may influence its uptake into 
the body.  However, it is also possible that such differences are 
real and can throw light on mechanisms of toxicity and/or of 
detoxication, thus making more intelligent assessment of toxicity 
possible.  It can be argued that the presence of the very toxic 
impurities in some formulations of diazinon (section 6.3.4) could 
have been deduced much earlier from differences in LD50 data.  
Likewise, the Pakistani poisonings due to strong potentiators in 
stored malathion (Baker et al., 1978) (section 6.3.4) might have 
been prevented, if more questions had been asked about the range of 
LD50 values given in the literature for malathion. 
Table 4.  Comparison of acute toxicity data for 
fenitrothion listed in evaluation reports of 
joint FAO/WHO meetingsa 
Animal              Sex    Route    LD50 (mg/kg 
                                    body weight)
 1970 Report

Mouse               M      oral     1336
Mouse               F      oral     1416
Mouse               M      ip       115
Mouse               F      ip       110
Mouse                      iv       220
Rat                 M      oral     740
Rat                 F      oral     570
Rat                 M      ip       135
Rat                 F      ip       160
Rat                        iv       33
Guinea-pig          M      oral     500
Guinea-pig                 oral     1850
Guinea-pig          M      ip       110
Guinea-pig                 iv       112
Cat                        oral     142

 1975 Report

Mouse               M      oral     1030
Mouse               F      oral     1040
Rat                 M      oral     330
Rat                 F      oral     800
Ring-neck pheasant         oral     34.5
Mallard duck               oral     2550
Dog                        oral     MLDb  681 mg/kg
Rat                 M      oral     940
Rat                 F      oral     600
a  From: FAO/WHO (1970b, 1975b).
b  MLD = minimum lethal dose.

6.1  Effects on the Nervous System

6.1.1  Effects attributed to interaction with esterases  Cholinergic effects

    (a)   Acute toxicity

    If non-ester herbicidal compounds are excluded, then the acute 
toxicity of all other organophosphorus pesticides shares the basic 
mechanism outlined in section 4.5.1, involving inhibition of AChE, 
accumulation of ACh, and over-stimulation of some central 
cholinergic neurons and of the sympathetic and parasympathetic 
nervous systems.  Signs and symptoms of poisoning are described 
fully in section 7.1.  Death is caused by respiratory failure due 
to a combination of blocking of the respiratory centre, 
bronchospasm, and paralysis of the respiratory muscles. 

    (b)   Chronic toxicity

    The cholinergic effects brought about by repeated 
administration of less than a single fatal dose are similar in type 
to the acute single-dose effects and are discussed in section 
6.3.1.  For the majority of these compounds, long-term feeding 
tests have been performed to establish the no-observed-adverse-
effect levels.  In every case, except bromophos-ethyl, the most 
sensitive indicator of an effect was depression of ChE activity in 
plasma or erythrocytes.  The phenomenon of tolerance to repeated 
doses of anticholinesterase compounds is covered in sections 6.3.1 
and 6.4.  For bromophos-ethyl, it has been reported that the 
urinary excretion of ascorbic acid and dehydroascorbic acid was 
slightly increased in beagle dogs given 0.39 mg/kg body weight 
daily, for 18 weeks, at which dose, depression of serum-ChE was not 
significant (FAO/WHO, 1973b).  Delayed neuropathic effects

    Delayed neuropathy has occurred occasionally in man and 
experimental animals after intoxication with a variety of 
organophosphorus esters.  The subject has been reviewed by Johnson 
(1975a,b, 1980, 1982a) and by Davis & Richardson (1980).  An 
account suitable for physicians is given by Lotti et al. (1984).  
Delayed neuropathy is not inevitably associated with intoxication 
by organophosphorus pesticides (Johnson, 1982a; Soliman et al., 
1982).  Improvements in the therapy of acute poisoning (section 
7.4) mean that higher doses of some organophosphorus insecticides 
can now be tolerated without fatal consequences.  However, many 
organophosphorus pesticides that might, theoretically, cause 
neuropathy, would only do so at a dose far above the lethal dose. 

    (a)   Characteristics

    Regardless of the severity of anticholinesterase effects, there 
is a delay after intoxication before neuropathic signs and symptoms 
appear.  In the adult hen, which is the test species of choice, 
this delay is 8 - 14 days, while in man, the delay may be up to 4 
weeks after acute exposure.  The first symptoms are often sensory 
with tingling and burning sensations in the limb extremities 
followed by weakness in the lower limbs and ataxia.  This 
progresses to paralysis, which, in severe cases, affects the upper 
limbs also.  Children and young animals are less severely affected 
than adults, but recovery is slow and seldom complete in adults; 
with the passage of time, the clinical picture changes from a 
flaccid to a spastic type of paralysis.  Cats, hens, and a number 
of larger species are affected by a single dose.  Repeated dosing 
does not reduce the delay in onset to less than 8 days from the 
first dose.  Baboons, monkeys, and marmosets do not respond easily 
to single doses of several typical neuropathic esters, and it is 
difficult to produce typical delayed neurotoxic effects in rodents, 
even by repeated dosing.  In early histological examinations, 
methods were used that showed mainly degeneration of the fatty 
myelin sheath surrounding long nerve axons and names such as 
"Organophosphate Demyelinating Disease" are still erroneously used, 
in spite of later work that showed that the nerve axon itself was 

primarily affected and damage to the myelin sheath was secondary 
(Cavanagh, 1954; Bouldin & Cavanagh, 1979).  The preparation of 
tissues and identification of lesions are described by Bradley 
(1976), Bickford & Sprague (1984), and by Prentice & Roberts (1984) 
in the Workshop Report edited by Cranmer & Hixson (1984).  This 
publication also covers many aspects of mechanism and testing. 

    (b)   Mechanism

    The first essential step in the initiation of the delayed 
neuropathic effect of an organophosphate is phosphorylation of a 
target protein in the nervous system.  The protein has esteratic 
enzyme activity.  The phosphorylation, which was originally studied 
radiochemically, can be monitored conveniently as progressive 
inhibition of the activity of this enzyme, which is now referred to 
as Neuropathy Target Esterase (NTE or Neurotoxic Esterase) 
(Johnson, 1980, 1982a).  The second, and equally essential, step is 
the transformation of the phosphorylated NTE to a modified form: 
one of the remaining ester bonds of the inhibitor molecule attached 
to the NTE active site undergoes a biochemical cleavage leaving an 
ionized acidic residue bound to the protein: this residue is 
negatively charged and the reaction is referred to as "aging".  
Both inhibition and aging of inhibited NTE are essential to 
initiate neuropathy, but the role of the negative charge in the 
initiation of axonal degeneration is not known. The process of 
"aging" of inhibited NTE has some analogy with the better-known 
"aging" of inhibited AChE.  However, the analogy does not last 
above the level of enzyme inhibition. Acute toxicity arises 
directly from the loss of catalytic activity of AChE, leading to 
accumulation of excess physiological substrate.  Mere loss of 
catalytic activity of NTE (without aging) does not initiate 
neuropathy (see below). There is no evidence of a deleterious 
accumulation of a physiological substrate for NTE or lack of 
hydrolysis products after inhibition  in vivo, and the effect of 
the negative charge may be focused on some quite separate process. 

    When NTE has been inhibited by a suitable phosphate, 
phosphonate, or phosphoramidate, aging is always possible, and this 
process has been shown to occur rapidly with a wide variety of 
neurotoxic esters and hen NTE.  However, after inhibition by 
phosphinates (which contain 2 phosphorus-carbon bonds) or by 
sulfonyl fluorides, no hydrolysable bonds remain in the attached 
inhibitor molecule.  Thus, aging is not possible, and these 
compounds are not neuropathic  in vivo.  Whenever hen NTE can be 
phosphinylated or sulphonated  in vivo, the birds become resistant 
to challenge doses of typical neuropathic esters, because the 
2-step initiation process has been blocked halfway.  Similarly, 
carbamates do not form aged inhibited enzymes and are either 
totally without effect (anti-cholinesterase carbamates are poor 
inhibitors of NTE) or inhibit the enzyme, but do not age.  Thus, 
they protect the hen in the same way as the phosphinates.  Now that 
this mechanism is understood, it is obvious that carbamates need 
not be subjected to tests that were designed to detect delayed 
neuropathic potential in organophosphorus anticholinesterase 

    The events that follow inhibition and aging of NTE are not 
known, but it is clear that, in adult hens, detectable delayed 
neuropathic events (clinical or histological) are never seen after 
a single dose/exposure of an organophosphorus ester, unless there 
is at least 70% (probably 80 - 90%) inhibition of the NTE in the 
brain and spinal cord soon after dosing (4 - 40 h).  Owing to the 
synthesis of fresh protein, this inhibition declines markedly 
during the 8 to 14-day delay period, and there is no correlation 
between neuropathy and NTE inhibition measured at the time that 
clinical signs reach their peak.  NTE has been found in the nervous 
tissue of all mammals and birds examined and can be inhibited, even 
in species such as the rat, in which there is no obvious clinical 
neuropathic response to a single dose.  It has been shown recently 
that, when single doses of certain neuropathic organophosphorus 
compounds are given to rats, degenerative lesions develop in their 
peripheral nerves and spinal cord. Although these lesions are 
similar to those in ataxic hens, they are not accompanied by 
clinical signs.  The dose-response of NTE inhibition and the 
neurological damage in rats are well correlated, and, as in hens, 
the lesions are prevented by protectively predosing the rats with 
sulfonyl fluoride (Padilla & Veronesi, 1985; Veronesi & Padilla, in 
press). Human NTE has been examined  in vitro (Lotti & Johnson, 
1978), and its response to inhibitors is similar to that of the hen 
enzyme (I50s differed by not more than 4-fold).  What is not known 
is the numerical value of the threshold of inhibition of NTE in man 
that is associated with clinical neuropathy. However, it is known 
that numerous people treated only with atropine for poisoning by 
trichlorfon have survived and then developed neuropathy (Johnson, 
1981a).  In contrast, it is very difficult to produce neuropathy 
with trichlorfon in the hen, without enormous doses coupled with 
prophylaxis as well as therapy for severe anticholinesterase 
effects.  It seems, therefore, that in the case of this pesticide, 
the chances of a severely poisoned man developing neuropathy rather 
than dying are greater than those of the hen.  It might be deduced 
that the threshold level of NTE inhibition for neuropathic effects 
in man is somewhat less than the 70% value for hen, and caution 
should be applied in the extrapolation from hen tests.  This 
argument is merely a comparison of the two hazards, death and 
neuropathy: it does not give any guide to the relative dose 
required to intoxicate man and hen. 

    (c)   Delayed neurotoxicity testing

    Two distinct procedures are currently practiced by testers, and 
each depends on the anticipated hazard.  In acute tests, it is 
recommended that hens surviving an LD50 test (preferably a test in 
which the therapeutic use of atropine raised the LD50) should be 
observed for three weeks for abnormalities of gait and then be 
re-dosed and watched for a further three weeks, after which a 
thorough histological examination of the distal ends of neurons in 
the spinal cord and peripheral nerve should be performed.  Long-
term neurotoxicity tests require feeding hens for up to 90 days 
with doses in the diet ranging up to those causing obvious adverse 
cholinergic effects; evaluation is by the same criteria as for the 
acute test.  It may be argued that long-term tests should be 

omitted, in view of the greater speed and simplicity of the acute 
test in obtaining yes/no answers and the fact that no pesticidal 
compound has ever been found to give a positive clinical response 
in feeding trials when negative in the 2-massive-doses test.  The 
practice in the United Kingdom has been to voluntarily exclude from 
agricultural use any compound shown to be neuropathic in acute 
tests.  Guidelines for the performance of acute and long-term 
delayed neurotoxicity tests are available (United Kingdom PSPS, 
1979; US EPA, 1982; OECD, 1983).  The OECD Guidelines point out 
that acute tests would be improved if they were accompanied by 
assays of NTE inhibition in the brain and spinal cord, one and two 
days after dosing.  Results of assays would provide graded dose-
response relationships instead of the present all-or-none scoring.  
Some examples are given in Johnson (1975b). Particularly useful are 
data such as those obtained with malathion (Johnson, 1981b), which 
showed negligible (< 10%) inhibition of NTE at the LD50 dose in 
hens.  These data indicate a different order of safety compared 
with that of some other compounds which caused 50 - 60% inhibition, 
though there was no visible clinical response.  A way to integrate 
the NTE test efficiently into delayed neurotoxicity test protocols 
has been suggested by Johnson (1984).  However, further discussion 
to improve this method is required. 

    (d)   Delayed neurotoxic response to long-term feeding

    For some neuropathic compounds, the potency of a single dose 
may be matched or even exceeded by the effect of the same amount 
spread over a few days.  In particular, compounds such as TOCP or 
leptophos, which are very poorly soluble in water and are required 
in a very large single dose to be effective, may well be absorbed 
with greater efficiency in a divided lower-dose regime.  However, 
the results of various studies (Johnson, 1982a) have shown that, as 
the dose is reduced further, there is a clear cut-off point below 
which there does not appear to be any cumulative effect.  Thus, 
TOCP in the diet of hens at 400 mg/kg produced neuropathy in 21 
days, while a level of 100 mg/kg diet did not cause any detectable 
clinical or histological damage after 140 days (Barnes, 1975).  
Monitoring of the NTE response to continuous feeding of non-
neurotoxic regimes of 2 organophosphates (0.125 mg DFP/kg for 5 
days per week, over 4 weeks, or 2.5 mg mono-2-cresyl diphenyl 
phosphate/kg, daily, for 10 weeks) showed that NTE levels in the 
brain and spinal cord were depressed within 2 - 3 weeks to about 45 
- 55% of normal and remained unchanged thereafter; the equilibrium 
is presumbably the result of daily synthesis matching daily 
inhibition.  These doses did not cause detectable neuropathy during 
either the feeding period or the 3 ensuing weeks (Lotti & Johnson, 
1980).  On the basis of these and other studies, Johnson (1982a) 
concluded that the hen nervous system might tolerate the 
biochemical defect of prolonged inhibition of NTE to about 50% 
normal level brought about by long-term dosing but could not 
tolerate the brief 80 - 90% inhibition that follows a single larger 
dose.  If long-term feeding tests in hens are required, then weekly 
measurements of the level of NTE inhibition should provide valuable 
predictive information, early in the test (Johnson, 1984).  Since 
it is necessary to kill birds for tissue sampling, more birds may 
be necessary, at least in the early stages. 

    (e)   Results of delayed neurotoxicity testing

    No pesticidal organophosphorus compounds, giving negative 
results in massive-dose tests, have caused delayed neuropathy in 
long-term feeding studies.  With the exception of trichlorfon, 
where 2 doses, 3 days apart, were necessary (Johnson 1970, 1981a), 
the massive-dose tests have been single doses given with 
prophylaxis and therapy (eserine + atropine and atropine + oxime - 
repeated if necessary) to ensure that doses above LD50 could be 
examined.  In Table 5, known pesticidal compounds are listed 
according to the doses known to produce marked-to-severe neuropathy 
in the majority of birds tested. Administration by either the oral 
or dermal route may be effective. 

    The review by Johnson (1975b) is believed to list all 
pesticidal and non-pesticidal compounds, or their derived oxons, 
tested and reported on, up to that time.  The JMPR Reports were not 
included as a literature source.  NTE responses are given where 
these have been measured.  Johnson (1982a) lists a number of 
pesticides for which both clinical and NTE tests had been reported 
since 1975 and notes that carbophenthion, cyanophos, diazinon, 
fenitrothion, malathion, methyl parathion, omethoate, and parathion 
can positively be declared non-neuropathic on the basis of 
negligible NTE inhibition responses, while chlorpyrifos, 
methamidophos, and salithion gave intermediate NTE responses 
without clinical expression at the doses tested.  Isofenphos 
( o -ethyl- o -2-iso-propoxycarbonylphenyl isopropylphosphor-
amidothioate) has been shown by NTE assays and clinical tests to 
cause delayed neuropathy in hens at about 20 x LD50 (Wilson et al., 
1984), while the insecticidal synergist  o-n -propyl- o -(2-propynyl) 
phenylphosphonate was neuropathic by both criteria at about the 
LD50 (Soliman, 1982). 

Table 5.  Organophosphorus pesticides causing delayed neuropathy 
in hens after a single dose
Compound                        Dose (mg/kg)   Reference
                                and route
mipafox                         25 im          Bidstrup et al. 
  N,N -diisopropylphosphoro-                    (1953)
 diamidic fluoride

haloxon                         1000 oral      Malone (1964)
 bis-(2-chloroethyl) phosphate

EPN                             40-80 sc       Witter & Gaines 
trichlornat                     310 oral       Johnson (1975b)

ethyl 2,4,5-trichlorophenyl     300-400 oral   Johnson (1975b)

ethyl 2,4-dichlorophenyl        > 2000 oral    Abou-Donia et al. 
 phenylphosphonothioate                        (1979)

leptophos                       400-500 oral   Abou-Donia et al. 
                                               (1974); Johnson 
desbromoleptophos               60 oral        Johnson (1975b)

 S,S,S -tributyl phosphoro-      1110 sc        Johnson (1970)
 trithioate (DEF)

cyanofenphos                    > 100 oral     Ohkawa et al. 
isofenphos                      100 oral       Wilson et al. 
  O -ethyl  O -2-isopropoxy-                     (1984)
 carbonylphenyl isopropyl-

 O-n- propyl  O -(2-propynyl)     400 oral       Soliman (1982)

dichlorvosb                      100 scc         Caroldi & Lotti 
amiprophos                      600 oralc,d     Huang et al. 
  O -ethyl  O -4-methyl-6-                       (1979)
  N- isopropylphos-

Table 5 (contd.)
Compound                        Dose (mg/kg)   Reference
                                and route

coumaphos                       50 oralc        Abou-Donia et al. 
                                500 dermal     (1982)

chlorpyrifos                    150 oral       Lotti et al. 
salithion                       120 oral       El-Sebae et al. 
a   Dose needed to cause marked-to-severe neuropathy in the 
   majority of birds tested.
b   50% formulation in hydrocarbons: dose calculated as active 
c   Mild neuropathy only at maximum tolerated dose.
d   Test performed in cockerels.

    The statement by Namba et al. (1971) that chlorpyrifos produced 
neuropathy in hens seems to have been without foundation and may 
arise from the misreading of a report by Gaines (1969), which 
mentioned that chlorpyrifos caused a rapid onset short-term 
weakness (sometimes called paralytic effect) similar to that caused 
by malathion.  However, one recent case of human poisoning and 
laboratory tests with doses well above the unprotected LD50 have 
shown neuropathic effects from this pesticide (Lotti & Moretto, in 

    (f)   Structure/activity relationships

    As noted above, not all organophosphorus pesticides cause 
delayed neuropathy.   In vivo tests and target-enzyme studies 
listed by Johnson (1975b) can be condensed according to a number of 
factors as listed by Johnson (1980, 1982a): 

    (1)  Factors that increase delayed neurotoxicity potential more 
than acute toxicity are: 

    (a)  choice of phosphonates or phosphoramidates rather
         than analogous phosphates;

    (b)  increase in chain-length or hydrophobicity of R1  and
         R2 ; and

    (c)  a leaving group X, which does not sterically hinder
         approach to the active site of NTE;

    (2)  Factors that decrease the comparative potential are:

    (a)  the converse of (1) a, b, and c;

    (b)  choice of R or X groups that are very bulky
         (naphthyloxy) or non-planar;

    (c)  choice of a nitrophenyl group at X (a steric effect?);

    (d)  choice of comparatively more hydrophilic X groups
         (oximes or heterocyclics); and

    (e)  choice of thioether linkages at X.

    Considering these factors, it can be seen why malathion and 
diazinon are both far below the neurotoxicity hazard line, why, in 
its homologous series, only dichlorvos is not neurotoxic at the 
LD50, why EPN, a phosphonothioate with a hydrophobic phenyl group 
at R1  is neurotoxic, even with a 4-nitrophenyl leaving group, and 
why it is not surprising that other phenylphosphonothioates such as 
desbromoleptophos, or cyanofenphos are also neurotoxic.  The 
apparent non-neurotoxicity of the ethyl analogue of leptophos 
(Hollingshaus et al., 1979) seems to contradict (1-b) above, but 
the dominant factor seems to be the problem of absorption of this 
very poorly soluble compound after oral dosage (Hansen & Hansen, 

6.1.2  Behavioural and other effects on the nervous system

    The problems of interpreting behavioural changes in relation to 
inhibition of AChE and the time-dependent changes in these 
variables have been discussed by Bignami (1976) and Bignami et al. 
(1975).  It appears that some learned responses may be acquired 
more quickly by rats recovering from an inhibitory dose of, e.g., 
DFP (1 mg/kg body weight).  This may be a sign of changed 
inhibitory responses in learning pathways, but it is difficult to 
say whether it can be classified as a toxic response. 

    Numerous research workers have reported changes at doses that 
affect levels of AChE, but without overt signs of intoxication.  
For example, Kaloyanova-Simeonova (1961) noted that small doses of 
chlorthion (5 or 10 mg/kg body weight in the rat) intensified 
conditioned motor reflexes and depressed them at higher doses: ChE 
levels were depressed in all cases and were restored more slowly 
than the return to normal reflex activity.  Reiter et al. (1975) 
did not find any effects on performance of learned visual 
discrimination tasks by monkeys at doses of parathion of 0.5 mg/kg 
body weight, which depressed blood levels of AChE by about 25% and 
those of pseudoChE by about 35%.  Doses causing 40% or more 
inhibition of AChE were associated with decreased responses, which 
returned to normal faster than the recovery of AChE levels.  A very 
sensitive response to the nerve agent soman (pinacolyl 
methylphosphonofluoridate) was reported in one out of several 
behavioural tests by Wolthuis & Vanwersch (1984).  In an open-field 
test, a number of performance variables were affected by a dose of 
only 3% of the LD50.  Effects were also seen with doses of 4 - 6% 
LD50 of 2 carbamates but not below 30% LD50 of the pesticide, TEPP, 
or of another nerve agent, sarin (isopropyl methylphosphono-
fluoridate).  Unfortunately, the effects on ChE levels were not 
measured.  There is no obvious reason for the contrasting effects 
of TEPP and sarin, on the one hand, and of soman and physostigmine, 
on the other.  The authors noted that, judged by poisoning signs at 
near-lethal doses, soman exerted a greater proportion of its 

effects centrally than the other 2 organophosphorus esters. The 
fact that changes may be seen in some, but not all behavioural 
responses at a certain dose emphasizes the statement by Revzin 
(1983) that no single behavioural or neurophysiological test can 
give a definite conclusion about organophosphate toxicity. 

    There appears to be only one other report in the literature of 
a behavioural change in animals at doses less than those that 
inhibit ChEs (Desi et al., 1971).  Behavioural and EEG changes were 
noted in rats fed bromophos at 500 or 100 mg/kg diet for 6 weeks, 
doses that also caused ChE inhibition, but, at 30 and 10 mg/kg, 
there were no effects on ChE, though some behavioural changes were 
still observed.  It is not clear whether undosed animals were 
handled in precisely the same fashion as the dosed. 

    However, in contrast to the above, Desi (1983) reported tests 
applied after 3 months of daily consumption of diet containing 
various percentages of the LD50 of bromophos.  The lowest 
concentration that produced changes in a behavioural test (maze 
running) and in EEG (both the complex EEG and computer-analysed 
segments of the EEG) was about 0.26% of LD50, daily, but this also 
caused significant changes in erythrocyte-AChE and plasma-ChE.  
Among 6 organophosphorus pesticides assessed by these procedures, 
none produced changes greater than that caused by the vehicle alone 
without also causing effects on ChE.  This conclusion differs from 
that written by the author. 

    Analysis of the EEG records of a small group of rhesus monkeys 
has been carried out both before, and one year after, intoxication 
with the potent anticholinesterase agent sarin (isopropyl 
methylphosphonofluoridate) (Duffy & Burchfield, 1980).  Three 
animals received a single "large dose" (5 µg/kg body weight iv), 
and 3 others received a series of 10 injections of 1 µg sarin/kg 
body weight im at weekly intervals: there were 10 controls.  The 
"large dose" animals had generalized convulsions and were 
maintained on Gallamine relaxant with artificial respiration; 
small-dose animals were considered in pilot studies to be near the 
threshold of poisoning, but showed few overt signs; they did not 
receive relaxant or artificial respiration.  Twenty-four hours 
after a "large dose", marked differences were seen in the EEG 
frequency spectrum, which is not surprising.  However, one year 
after the dose, there was still a small increase in the percentage 
energy in the beta-2 region of the spectrum and the change was said 
to be statistically significant.  Some changes in the beta region 
were detectable in all 6 dosed monkeys one year after; no 
significant changes were seen in the 10 controls.  However, 
apparently the changes were only seen under some lighting 
conditions and were small compared with differences between the 
frequency spectra of the only 2 controls for which data were shown.  
The statistical treatment of the acquired data seems valid, but the 
actual values measured one year after dosing are obviously well 
within the normal range.  No indication was given of how much 
variation can be caused in the pattern of undosed animals by 
variations in the conditions of handling and observation, or what 
the range is for apparently identically treated normal animals. The 

doubts pertaining to the toxicological significance of these 
measurements apply also to some human studies using the same 
technique (section 7.2.2). 

    Effects of cholinergic agents on the visual system have been 
monitored by Revzin (1980).  In urethane-anaesthetised pigeons with 
implanted electrodes, various changes in the response of specific 
neurones of the optic tectum and of the hippocampus were noted 
after doses both of mevinphos and of atropine.  The author claims 
that the procedure was sensitive in detecting effects in the 
absence of detectable peripheral parasympathetic signs.  However, 
the lowest effective dose of mevinphos was only one-third of that 
(0.15 mg/kg body weight) which produced parasympathetic signs that 
would certainly be associated with substantial inhibition of AChE.  
Thus, the claim to sensitivity of this complex procedure in 
surgically modified birds seems excessive. 

    Some possible effects of anticholinesterases on non-
cholinesterase targets were considered by O'Neill (1981).  No clear 
effects seem definable at concentrations lower than those that 
inhibit AChE and some are probably secondary to stimulation of non-
cholinergic nerves with cholinergic innervation.  However, an 
endopeptidase that can hydrolyse putative transmitter peptides in 
the nervous system is known to be inhibited by di-isopropyl 
phosphorofluoridate at a concentration similar to that which 
inhibits AChE (Kato et al., 1980).  Thus, some involvement of non-
cholinergic pathways in the causing of CNS effects in 
organophosphate poisoning cannot be excluded.  Moreover, some 
anticholinesterases also exert effects directly at the cholinergic 
receptor as well as by the inhibition of AChE (Karczmar & Ohta, 

6.2  Other Effects

    A variety of histological lesions has been described at autopsy 
in animals severely poisoned with organophosphate pesticides.  
However, very few effects are described in the absence of obvious 
poisoning or at doses that do not markedly inhibit the ChEs.  In 
the following sections, the evidence is reviewed for effects not 
obviously attributable to inhibtion of either AChE or NTE. 

6.2.1  Mutagenic and carcinogenic effects

    The proposed theoretical basis for believing that dimethyl or 
diethyl phosphate pesticides might be mutagenic or carcinogenic 
has already been discussed (section 4.5.2).  This basis was shown 
to be defective by Bedford & Robinson (1972).  No alkylation was 
detected in N7  of guanine in RNA and DNA of liver of animals that 
were exposed for 12 h to working concentrations of dichlorvos of 
64 g/m3  (0.064 g/litre air) (Wooder et al., 1977); these authors 
contrasted their data with earlier published work showing modest 
alkylation of guanine in suspensions of cells exposed to very high 
solution concentrations of dichlorvos.   In vivo, the acute 
anticholinesterase effects limit the circulating concentration 
that can be tolerated by any mammal and there is also strong 

preference for phosphorylation of biological scavenger molecules 
rather than for alkylation built into the organophosphorus 
pesticide molecules. 

    It has frequently been suggested that dichlorvos has 
carcinogenic potential because of observed mutagenic effects in  in 
 vitro test systems.  The IARC (1979) Working Group accepted 
extensive data showing no evidence for the mutagenicity of 
dichlorvos in mammals.  FAO/WHO (1978b) accepted animal studies 
showing no dose-related carcinogenic effects in life-time studies 
carried out at doses that depressed blood-ChE levels. 

    In a 78-week feeding test on groups of 50 male and 50 female 
mice (B6 C3 F1  hybrid), no dose-related effects were seen when the 
diet contained about 600 or 300 mg dichlorvos/kg, respectively.  
The IARC Working Group evaluating this study noted that a few 
oesophageal tumours were seen in treated mice.  It appears that 
this fact influenced their verdict that "the available data do not 
allow an evaluation of the carcinogenicity of dichlorvos to be 
made" (IARC, 1979). 

    An IARC Monograph (1983) included evaluations of 5 widely-used 
organophosphate pesticides (malathion, methyl parathion, parathion, 
tetrachlorvinphos, and trichlorfon).  In several cases, the 
conclusions were that acceptable tests had been performed with no 
evidence of carcinogenic effects or of mutagenic effects in 
mammals.  For others, the conclusions were of "limited evidence" 
consisting of very small effects above the control background 
levels in life-time studies. None of these compounds was judged to 
be a strong mammalian mutagen or carcinogen and the same statement 
is true for all organosphosphorus pesticides that have been 
evaluated by FAO/WHO Working Parties or by other authorities.  
However, recent published results show that controversies do occur 
when evaluating the outcome of carcinogenicity studies.  Huff et 
al. (1985) reevaluated the pathology of the original  studies by 
the US National Cancer Institute in 2 different strains of rats.  
Histopathological reexamination confirmed the earlier conclusions 
that malathion and malaoxon were not carcinogenic. These 
conclusions differed from those of Reuber (1985) who evaluated the 
same studies and rated both compounds as carcinogenic. 

6.2.2  Teratogenic effects

    Defects in the development of fertilized hen eggs, injected 
with various organophosphates, are known, but many of these are 
associated with the inhibition of the enzyme kynurine formamidase 
and a depression of NAD levels at a critical period of development 
(Seifert & Casida, 1980).  This pathway is not critical in mammals, 
and no equivalent effects are known.  If teratogenicity is taken to 
mean induction of malformations in live offspring without decrease 
in number of births (i.e., no embryotoxicity), then for the vast 
majority of organophosphorus pesticides, no adverse effects of 
continuous feeding of organophosphates on pre- or postpartum 
mortality have been reported, nor have embryonic defects been 
proved, except at doses that significantly retarded growth in the 
mother (Vergieva, 1983).  Single high doses causing significant 

toxic effects in mothers may be deleterious: a number of these 
toxicity-linked effects have been summarized by Seifert & Casida 
(1980).  Kimbrough & Gaines (1968) reported deaths, and that 
resorptions were increased in pregnant rats given a single high 
dose of parathion or diazinon on the 11th day of gestation.  
However, these effects were associated with significant toxic 
effects on the mothers. Similarly, trichlorfon at very high doses 
(400 mg/kg per day with the dose divided into 3 spaced aliquots) 
and given on days 6 - 15 of gestation, produced defects in 
offspring: each dose produced cholinergic symptoms; no effects were 
seen in rats, mice, or hamsters when the daily dose was 200 mg/kg 
(Staples & Goulding, 1979).  However, a specific defect consisting 
of hypoplasia of the cerebellum in offspring was noted, both in 
field cases and experimental tests, 8 pregnant pigs were dosed once 
or twice with neguvon (a veterinary grade of trichlorfon) between 
days 55 and 70 of pregnancy (Knox et al., 1978).  Doses were 50 - 
60 mg/kg body weight, which caused maximum inhibition of 
erythrocyte-ChE levels of 40 -80%, without overt signs of 
poisoning.  The hypoplasia was accompanied by severe ataxia and 
tremors, while voice and vision appeared unaffected.  No defects 
were seen in the offspring of over 100 control sows housed with the 
dosed animals, and serological and virological tests did not show 
anything incriminating.  A genuine teratogenic effect of moderate 
doses of trichlorfon commonly used in veterinary practice has been 
demonstrated in the pregnant pig.  However, it may be that the 
herds tested were unusually susceptible, since (apparently) 
congenital tremor had been known in litters borne over many years 
in the area where the trichlorfon-induced effects were seen. 

6.2.3  Effects on the immune system

    In a review, Zackov (1983) stated that "most ... organo-
phosphorus pesticides elicit autoimmune reactions and suppress the 
production of antibodies against vaccines".  No evidence was given 
and it is not clear whether the statement was claiming specific 
effects or referred to doses that are sufficient to produce a range 
of toxic effects. 

    Shtenberg et al. (1974) claimed that oral doses of methyl-
nitrophos (fenitrothion) or chlorphos (trichlorfon) at 5 or 7 mg/kg 
body weight per day, for an unspecified period, suppressed 
haemaglutinin levels in rats immunized against sheep red blood 
cells; these doses would have significantly inhibited ChEs and were 
said to be more effective in rats fed a protein-deficient diet.  
Dandliker et al. (1979) reported a depression in antibody titre in 
rats in the 6 - 7 weeks of an immunization procedure that commenced 
either one day before or one day after (both statements are made) 
an oral dose of half of the LD50 of parathion.  The immunization 
consisted of weekly intramuscular doses of 400 µg fluorescein-
labelled ovalbumin with Freunds Complete Adjuvant.  The confusion 
concerning the order of intoxication and primary immunization is 
very important when such a high dose was given, since cholinergic 
symptoms, fluid loss, imbalance, and general debility would have 
been marked.  Administration to mice of 0.1 x LD50 of parathion for 
8 days led to a 10% loss in body weight.  Immunization on the 9th 
day showed a statistically-significant (34%) reduction in the 

number of antibody plaque-forming cells derived from the spleen, 4 
days after immunization, but the reduction was insignificant (10% 
only) when immunization was carried out on day 10, though several 
animals in the group died at this point due to accumulated toxic 
effects (Wiltrout et al., 1978). 

    Some decreased antibody titres "proportional" to AChE 
inhibition were noted in response to prolonged doses of malathion 
or dichlorvos (0.025 - 0.4 x LD50 given 5 days per week for 6 
weeks) (Desi et al., 1978).  Clearly, none of the above responses 
can be dissociated from the general cholinergic intoxicating 
effects of the pesticides.  There do not appear to be any reports 
of studies on the immunological status of healthy animals receiving 
doses causing little or no depression in ChE levels. 

6.2.4  Effects on tissue carboxyesterases

    A variety of carboxyesterases abound in serum, liver, 
intestine, and other tissues (section 4.4).  Although inhibition of 
one specific carboxyesterase (NTE) has toxic sequelae (section, no direct deleterious effects of inhibiting other 
carboxyesterases have been demonstrated. However, they may 
contribute markedly to the metabolic disposal of malathion and 
certain other organophosphorus pesticides, so that inhibition of 
tissue carboxyesterases may potentiate the toxicity of such 
pesticides (section 6.3.5). The structure/activity relationships 
for inhibition of these enzymes by organophosphorus compounds 
inevitably differ from those for inhibition of AChE.  For EPN and 
fenchlorphos, both serum- and liver-carboxyesterases of rats were 
markedly more sensitive than brain- and serum-AChE; in other cases, 
the liver enzymes, but not those in serum, were more sensitive (Su 
et al., 1971). 

6.2.5  Sundry other effects of organophosphorus pesticides

    Very few effects other than those described in the sections 
above have been noted, except those arising from ill-health due to 
severe anticholinesterase effects.  Thus, impaired growth rate is 
commonly associated with a rapid depression in AChE levels to less 
than 50%, but much lower levels can be tolerated without ill-
effects, if the depression is brought about over several weeks, and 
then maintained for up to a year (section 6.3.1). 

    Various changes in glucose metabolism, in serum enzymes, and in 
other clinical chemical variables have been reported after single, 
acute, or repeated doses of various pesticides at from one-tenth to 
one-quarter of the LD50, daily (Dimov & Kaloyanova, 1967; Enan et 
al., 1982). 

    A reversible, mild muscle-necrotising effect could be detected 
histologically in the diaphragm muscles of rats, 24 h after a dose 
of paraoxon, parathion, or other anticholinesterases, sufficient 
to cause marked fasciculations (Fenichel et al., 1972; Dettbarn, 
1984).  The damage appeared to be a function of the prolonged 
cholinergic stimulation of the muscle, since it was entirely 

prevented by doses of atropine, which prevent fasciculations, or by 
alpha-bungarotoxin applied directly to the myoneural junction 
(Salpeter et al., 1979). 

    Several adverse effects attributed only to certain 
organophosphorus esters are listed below.  The list may be of value 
in promoting more careful examination of intoxicated animals or 
human beings.  Effects on hormones

    Changes in the diurnal pattern of plasma-ACTH and adrenal 
levels of some related enzymes have been reported in rats 
maintained with dichlorvos in the drinking-water at 2 mg/litre: 
blood-ChE levels were not affected (Civen et al., 1980).  However, 
the weight gain of the treated animals was only half that of the 
controls, and the fluid consumption was increased by 20%.  These 
deleterious effects could be due to diarrhoea and imbalance of 
fluids with inevitable repercussions on hormonal levels, etc.; 
preferential effects of the dichlorvos on intestinal esterases 
might be the primary effect.  Effects on the reproductive system

    Damaged seminiferous tubules were reported in mice given either 
a single dose of about half of the LD50 of dichlorvos or 18 doses 
of about one-tenth of the LD50 (Krause & Homola, 1974).  However, 
the doses were high, the percentage increases seem small, and the 
number of samples taken was very small; thus, no statistical 
evaluation is possible.  Amiprophos has been reported to cause some 
gonadotrophic effects in adult cockerels (Huang et al., 1979), but 
details are few.  Effects on the retina

    Fenthion administered intramuscularly at about one-quarter of 
the LD50 (50 mg/kg body weight), every 4 days for one year 
(solvent, if any, not stated), affected the electroretinogram in 2 
strains of rats (Wistar and black Long-Evans) within 3 months and 
abolished it after one year (Imai, 1977). Similar studies involving 
the administration of either fenitrothion or ethylthiometon to 
beagle dogs for 5 days per week for 2 years, were reported by 
Ishikawa & Miyata (1980).  Doses that depressed plasma-ChE levels 
to about 30% of normal, throughout the period, led to changes in 
optical function after 13 months continuous exposure and to 
morphological changes in the ciliary muscle at termination.  Porphyric effect

    Daily application of technical (85%) diazinon (20 or 40 mg/kg 
body weight) to the skin of Dark Agouti rats just above the tail 
produced a 4-fold increase in faecal porphyrins, after 8 - 12 weeks 
(Bleakley et al., 1979).  There was no increase in urinary 
porphyrins and no effect when diazinon was given in food (about 
8 mg per day to rats, initially weighing 180 g).  The pattern of 
porphyrins excretion was said to be indistinguishable from 

porphyria cutanea tarda.  However, the increase in excreted 
porphyrins in classical porphyria cutanea tarda may be as much as 
1000-fold, with massive amounts in the urine as well as in the 
faeces.  The authors failed to reproduce even this small effect in 
rats when they used more pure (97%) diazinon (Nichol et al., 1982).  
However, they also found that an impurity in stored technical 
material, isodiazinon (diethyl 2-isopropyl-6-methyl-4- S -
pyrimidinyl phosphorothioate), was very effective in causing 
porphyrin accumulation, when added to cultures of chick 
hepatocytes; confusingly, however, the accumulated porphyrin was 
coproporphyrin rather than the expected protoporphyrin.  Although 
human poisoning with diazinon is not uncommon, there has only been 
one report implicating technical diazinon in a few cases of 
porphyria cutanea tarda in occupationally-exposed workers (Bopp & 
Kasminsky, 1975). Further experimental animal studies seem 
warranted.  No reports have been found of porphyria connected with 
exposure to other organophosphorus pesticides.  Lipid metabolism

    Organophosphate esters can inhibit the activities of some 
triglyceridases and lipases  in vitro and  in vivo.  However, no 
repercussions from such inhibition were found when appropriate 
parameters were measured in rats fed for one year with either of 2 
pesticides that caused marked (60 - 80%) depression of blood-ChE.  
Thus, male or female rats were fed either a normal diet or a diet 
enriched sufficiently with fat to increase aortic fatty acids by 
170%.  No changes occurred in: the hormone-sensitive lipase and 
lipoprotein lipase in adipose tissue; the free and total fatty 
acids and total glycerol and total cholesterol in serum; and the 
total fatty acids, cholesterol, and glycerol in the aorta (Buchet 
et al., l977). The pesticides were chlorpyriphos (100 mg/kg diet) 
and triamiphos (10 mg/kg) and the findings were contrary to those 
from a preliminary study by the same workers.  Effects causing delayed deaths

    Although not pesticidal agents themselves, two of the 
phosphorothiolate impurities found in technical malathion and some 
analogues of these impurities caused delayed effects, which were 
lethal for rats at doses below the cholinergic LD50 (Aldridge et 
al., 1979; Mallipudi et al., 1979; Verschoyle et al., 1980).  The 
compounds were  O,O,S -trimethyl phosphorothioate (I),  O,S,S -
trimethyl phosphorodithioate (II), and the ethyl analogues (III and 
IV).  After an oral LD50 dose (as low as 26 mg/kg body weight for 
II), all 4 compounds produced cholinergic responses that lasted 
less than 24 h and deaths at this time were only seen with IV: 
doses 2 - 6 x LD50 were needed to cause cholinergic deaths with I - 
III.  Rats dosed at, or near, the LD50 recovered from the initial 
cholinergic effects, but by day 3, they had lost weight and were 
panting with laboured respiration; deaths occurred 3 - 6 days after 
dosing.  However, survivors appeared normal, 10 days after dosing.  
Death was due to pulmonary insufficiency associated with 
progressive cell proliferation (Dinsdale et al., 1982; Imamura et 
al., 1983; Aldridge & Nemery, 1984), and combined therapy with 
atropine and oxime was ineffective.  The biochemical mechanism of 

these effects is not fully known, but it is probable that the 
proximal toxin is produced in the lung by oxidative attack on the 
alkylthio moiety of the compounds (Aldridge et al., 1985).  The 
activities of brain-AChE and plasma-ChE and carboxylesterase, which 
were partially inhibited during the first day after dosing, 
increased thereafter and were at least 50% of the levels of 
activity in the controls at the time of death.  The margin between 
delayed death LD50 and cholinergic LD50 was markedly less with the 
triethyl, than with trimethyl compounds.  Such effects were seen 
with  S,S,S -trimethyl phosphorotrithiolate but not with the higher 
analogue ethoprophos ( O -ethyl  S,S -di- n -propyl 
phosphorodithiolate) or with methamidophos (Verschoyle & Cabral, 

    A different form of delayed acute toxicity was reported to 
occur 4 days after large oral doses of DEF in hens.  The effect was 
not seen after a single dose, sufficient to cause delayed 
neurotoxicity, was given subcutaneously (Johnson, 1970) or dermally 
(Abou-Donia et al., 1980).  The effect was distinct from both 
cholinergic and delayed neuropathic effects and is attributed to 
the acute toxicity of  n- butyl mercaptan produced by the degradation 
of DEF in the gastrointestinal tract.  Selective inhibition of thermogenesis

    The defoliant DEF ( S,S,S -tri- n -butyl phosphorotrithiolate) 
acted as an anticholinesterase at high doses, but, at lower doses 
(60 - 200 mg/kg in rats and mice), it caused a profound fall in 
body temperature (as much as 10 °C over a few h), without marked 
sedation; deaths occurred mostly after the depression had persisted 
for a day (Ray, 1980).  The effect was different from the smaller 
atropine-sensitive changes due to some cholinomimetics and was due 
to blocking of cold-induced thermogenesis without affecting heat 
conservation mechanisms.  The effect seems unique to the DEF 
chemical structure.  Ray & Cunningham (1985) demonstrated that the 
effect was a selective action on a central thermogenic control 
mechanism rather than on peripheral thermogenic processes and that 
it was probably due to a metabolite of DEF rather than to the 
parent compound. 

6.3  Factors Influencing Organophosphorus Insecticide Toxicity 

6.3.1  Dosage-effect

    The lethal effects of organophosphorus insecticides are due to 
severe cholinergic effects arising from excessive inhibition of 
AChE.  With few exceptions, the AChE activity of the tissues is 
inhibited soon after the administration of acutely toxic doses of 
all anti-AChE agents. This is true, not only for compounds that do 
not require metabolic conversion to anti-AChE agents, but also for 
most phosphorothioates, phosphorodithioates, and 
phosphorodiamidates that are oxidized by the liver to metabolites 
with anti-AChE activity.  In general, the duration of action of 
most anti-AChE agents is relatively short, as evidenced by 
considerable reversal of the inhibition within a few days.  For 

this reason, a 10-day observation period is sufficient for acute 
LD50 measurements on all anti-AChE agents that have been studied, 
and 2 days suffice for most. 

    The data in Table 6 give a comparison of the maximal amount of 
inhibition of the ChE activities in the brain, submaxillary glands, 
and serum of rats for several compounds, all of which were given at 
dose levels equivalent to 5/8 of the LD50.  The time at which 
maximal inhibition occurred and the period required for complete 
reversal of the inhibition are also presented.  From these 
examples, it can be seen that, in general, equivalent fractions of 
the LD50 of various anti-ChE compounds produce similar levels of 
inhibition of ChEs, though the LD50 values for the various 
compounds differ considerably.  The time at which maximal 
inhibition of ChEs occurs varies from 15 min to 3 h after 
administration.  In some cases, the AChE activity of the brain and 
parasympathetic nervous system, as indicated by the submaxillary 
gland, and the non-specific ChE of the serum are inhibited to the 
same extent by a particular compound.  However, notable exceptions 
are OMPA, which is converted in the liver to a very labile 
inhibitor that never reaches the brain, and Guthion, which does not 
inhibit non-specific ChE. 

    Differences between the responsiveness of rat brain- and serum-
ChE have been reported also in the case of dietary administration 
of various organophosphorus  insecticides (Su et al., 1971).  Thus, 
a level of only 40 mg EPN/kg fed for 1 week reduced brain-ChE to 
50%, while 125 mg/kg was needed to achieve the effect in serum; the 
sensitivity was reversed for fenchlorphos, while the sensitivities 
of the 2 tissues were similar for demeton. It is not clear whether 
these differences reflect differences in access of the compounds to 
their targets, differences between the tissue AChEs, or the fact 
that pseudoChE is present as well as AChE in the serum of rats, so 
that assay of the hydrolysis of ACh using serum measures both 
enzymes, whereas, in the brain, the activity is about 90% specific. 

    Marked differences in the rate of reversal of the inhibitory 
effects on ChEs of different compounds,  in vivo, are shown in Table 
6.  In view of the variable duration of action of various anti-ChE 
agents, the performance of assays on the tissues of animals at 
intervals after acutely toxic doses provides a great deal of useful 
information regarding the toxicity of these compounds.  The 
transition from a tolerable to a lethal dose (either acute or 
chronic) often occurs within a 2 to 4-fold range.  This is not 
surprising, since the AChE of nervous tissue and effector organs 
must be inhibited by 50 - 80% before pharmacological effects can be 
seen (Holmstedt, 1959).  The increment in dose to raise inhibition 
to 90% with associated deaths is not very great. 

Table 6.  Onset and duration of the anticholinesterese action
of some organophosphorus compounds in ratsa 
Compound                 Maximum inhibition of cholinesterase (%)      
                     Dose    Brain  Serum  Sub-       Time to  Time to      
                     (mg/kg                maxillary  maximum  complete     
                     body                  gland      inhib-   reversal     
                     weight)                          tion (h) (h)          
Iso-Systox           1.0     85     80     75         3.0      120          
 (demeton- S )b                                                          
Disyston             1.25    75     85     75         3.0      120          
Guthion              3.5     60     0      50         0.5      24           
Dipterex             140.0   85     82     85         0.25     6            
Octamethyl           5.0     0      85     88         2.0      144          
 tetramide (OMPA)c                                                      
a   From: DuBois (1963).
b   Phosphorothioic acid,  O -[2-(ethylthio)ethyl]  O,O -diethyl ester.
c   Octamethylpyrophosphoramide.

    The general correlation of inhibition of ChE with symptoms of 
poisoning is also seen with repeated dosing with organo-phosphates, 
but details vary greatly.  It is always true that a prerequisite of 
death is profound inhibition of AChE in the central and/or 
peripheral nerves, but the tolerable maximum inhibition increases 
when this level is reached, stepwise, over a period of 2 - 4 weeks 
or more.  Thus, when commercial Systox (containing about equal 
amounts of the  O - and  S -isomers of demeton) was fed to rats at 
20 mg/kg diet, there were no signs of poisoning, though, at the end of 
16 weeks, the brain- and whole blood-ChE activities were 26 and 28% 
of normal, respectively (Barnes & Denz, 1954).  At 50 mg/kg, 3 out 
of 12 rats died, but all others in the group improved after initial 
marked signs of poisoning during the first month, their food intake 
increased above normal (and therefore their actual dose increased), 
and their growth rate became normal.  This improvement was not due 
to any marked increase in ability to detoxify the agent, since, at 
the end of 16 weeks, these apparently healthy rats had only 7 - 8% 
of normal AChE activity in the brain and blood.  This level would 
be associated with fatalities if brought about by a single dose; 
indeed, at the end of the study, the animals were consuming daily a 
dose equivalent to 96% of the single-dose LD50.  In a similar way, 
Barnes & Denz (1951) found that parathion in the diet at 100 or 
75 mg/kg was lethal for the majority of rats in large groups within 
3 - 4 weeks, while results with 50 mg/kg were variable (26/72 deaths 
in one trial and 3/36 in a later trial) and no deaths attributable 
to poisoning occurred in groups fed 20 or 10 mg/kg.  The rats 
surviving 50 mg/kg showed clinical signs of intoxication (notably 
fasciculations) and ate less, initially: they ate normally after 3 
weeks, but failed to gain weight as rapidly as the controls.  
However, signs of poisoning decreased in severity and frequency 

during the third month and seldom reappeared during the remainder 
of a year's feeding.  This pattern of response and of adaptation is 
typical for all anticholinesterase pesticides.  When monitoring of 
enzymes is carried out in parallel with feeding, the level of 
activity often rises to a steady state after an initial decline.  
Factors determining the fraction of an LD50 dose that is tolerable 

    (a)  Speed of absorption, of subsequent metabolic activation, 
    and of elimination of the compound.  Thus, for demeton- S -
    methyl, much of the sulfoxide metabolite from a single dose 
    will still be circulating on the following day, though the 
    parent compound may not linger.  In such a case, lethal 
    concentrations will build up more easily than with, say, 
    trichlorfon, which is converted to the inhibitory dichlorvos, 
    both of which are rapidly eliminated; 

    (b)  The net rate of formation of a stable form of
    inhibited AChE arising from the 3 reactions of inhibition, 
    reactivation, and aging described in section 4.5.  The 
    relationship of the chemical structure of an oxon inhibitor to 
    rates of these reactions is complex and also varies between 
    species.  AChEs from the rat have not been purified and 
    subjected to extensive kinetic study  in vitro.  In most 
    studies, crystallized (not 100% pure) bovine erythrocyte-AChE 
    has been used.  Rates of spontaneous reactivation and aging for 
    this enzyme inhibited with dimethoxy, diethoxy, and ethoxy, 
    ethanthio-substituted phosphates are shown in Table 7. 

Although data derived in this way cannot be transposed directly to 
 in vivo situations, they are consistent with the well-known fact 
that, after poisoning by a sub-lethal dose of some dimethyl 
phosphates, recovery with the disappearance of symptoms is complete 
within a few h.  The value of k+3  for erythrocyte-ChE taken from 
rats dosed  in vivo with dimethyl phosphate, was reported to be 57 
x 10-4  (a half-life of inhibited enzyme of 2 h).  One day after 
such a sub-lethal dose, most of the rat AChE will again be in the 
uninhibited form with a small fraction in the aged inhibited form.  
In contrast, not more than half of the inhibited enzyme would be 
expected to be reactivated in one day after poisoning with diethyl 
phosphate and a substantial proportion of the inhibited enzyme 
would be aged, so that recovery to 100% activity would be a very 
slow process, depending on the synthesis of fresh enzyme.  It 
follows that markedly different outcomes would be expected from 
repeated intoxication with doses of dimethyl phosphate and diethyl 
phosphate which both caused an initial response of, say, 50% 
inhibition, the former would be less hazardous than the latter.  
This interpretation concurs with the fact that rats can survive 
daily doses of 25% of the LD50 of trichlorfon, but only about 12% 
of the LD50 of parathion (DuBois, 1963).  DuBois (1963) also 
pointed out that ChE inhibition mounted steadily as a result of 
daily doses of OMPA and that toxic effects were seen when 
inhibition reached about 70%.  It is believed that no spontaneous 
reactivation of ChE occurs after inhibition by phosphoramidates, 
which makes such compounds intrinsically undesirable as pesticides. 

Table 7.  Rates of spontaneous reactivation (k+3 ) and of 
aging (k+4 ) of bovine erythrocyte cholinesterase after 
inhibition  in vitro a 
          O                         Rate constants x 104  
          ||  R1                     (per min) at pH 7.4 
          || /                      and 37 °C
    Enz-O-P       substituents

R1                 R2                 k+3            k+4 
-OCH3              -OCH3              115           14

-OCH3              -SCH3              1170          95

-OC2 H5             -OC2 H5             2.0           2.2

-OC2 H5             -SC2 H5             270           32
a   From: Clothier et al. (1981).

    Dose-effect relationships for delayed neurotoxicity have been 
listed (Johnson, 1975b).  It has been noted that, as for 
cholinergic effects, levels of long-term dosing can be found that 
are detectable by a biochemical response at the primary target but 
have no clinically- or histologically-observable correlate.  The 
threshold of the tolerable response is probably a permanent 
inhibition or 40 - 50% of NTE (Johnson, 1982a). 

6.3.2  Age and sex

    It is well-known that the microsomal MFOs and other drug-
metabolizing enzymes are present at comparatively low levels in 
neonatal animals, but activity develops to approximately the adult 
level early in maturation.  Since MFOs are involved in both the 
activation and degradation of many organophosphorus pesticides 
(section 4.3), the likely net result in terms of LD50 is hard to 
predict.  One-day-old rats were 9 times more susceptible to 
malathion than 17-day-old animals (Mendoza, 1976).  The toxicity of 
methyl parathion and of parathion for rats decreased from birth 
through the developmental period: the decrease was best correlated 
with the increasing capacity of the animals to metabolize the 
oxygen analogues by both oxidative and hydrolytic pathways (Benke & 
Murphy, 1975).  The LD50 (ip) of trichlorfon in adult male rats was 
reported to be 250 mg/kg body weight, compared with 190 mg/kg in 
male weanlings (FAO/WHO, 1972b).  Whether this is a significant 
difference is not clear.  Liver MFO activity fluctuates according 
to the hormonal status of female animals. LD50 values quoted for 
males and females often differ, but these values generally arise 
from different laboratory animals subjected to many variable 
factors (including the purity of the test sample).  Among several 
representative pesticides surveyed for this review, only parathion 
showed a marked and apparently real difference in LD50s between the 

sexes, the oral LD50 in male rats being 5 - 30 mg/kg body weight, 
depending on the solvent, compared with 1.8 - 5 mg/kg in females 
(FAO/WHO, 1964). 

6.3.3  Nutrition

    It is well-known that liver MFO activity can be manipulated by 
administering a diet severely deficient in protein.  The 
consequences can be dramatic in terms of the toxicity of compounds, 
such as carbon tetrachloride, which undergo a single 
biotransformation step leading to a directly toxic product.  
However, as with the age and sex factors discussed above (section 
6.3.2), several metabolic steps may be affected. No clear-cut 
effects seem to have been reported. Thus, the acute toxicity of 
diazinon is greater (up to 2-fold) in rats maintained on a diet, 
either very low (4%), or very high (81%) in protein compared with a 
standard (29%) protein diet (FAO/WHO, 1971b).  A similar increase 
in toxicity is seen with naled ( O,O -dimethyl  O -1,2-dibromo-2,2-
dichloroethyl phos-phate) (Kaloyanova & Tasheva, 1983).  Boyd 
(1969) reported that, while increases in toxicity were 2-3 fold for 
diazinon, malathion, and demeton, the increase in parathion 
toxicity was 7.6 fold, in malnourished rats.  Whether the effects 
at such extremes were directly due to changes in the 
biotransformation of the agent or to the animals becoming generally 
unhealthy is not clear. 

6.3.4  Effects of impurities and of storage

    Insecticides are manufactured and formulated in various ways 
and in many countries.  There may be significant differences in 
these procedures and in the conditions of storage of formulated 
products.  These factors can influence the nature and extent of 
impurities present in the material that is ultimately applied. 

    Impurities in a pesticide may be of very low toxicity (the 
majority), may be toxic in their own right (more or less toxic than 
the major component), or they may be potentiators of the toxicity 
of another component.  Impurities toxic in their own right

    (a)   Non-anticholinesterase effects

    The most dramatic example of an impurity exerting an effect 
different from that of the principal component does not come from 
the realm of organophosphorus pesticides. The potent toxicant 
2,3,7,8-tetrachlorodibenzodioxin (TCDD) may be present in the 
herbicide 2,4,5-trichlorophenoxyacetic acid so that, even at a few 
mg/kg, the effects of the impurity may dominate the toxicological 
response. An analogous non-cholinergic response due to impurities 
is not known in anticholinesterase pesticides. Questions have been 
asked about the possible mutagenic effects of trimethyl phosphate, 
which may be present at a few percent in some technical 
preparations of dimethyl phosphates, but the possible exposure  in 
 vivo is limited by the main anticholinesterase response to the 

pesticide, and there appears to be no evidence for mutagenic 
effects in mammals of any organophosphorus pesticide (section 

    (b)   Anticholinesterase effects

    LD50 values for technical preparations of diazinon have varied 
over an unusually wide range.  The oral LD50 for the rat was 
reported to be 76 - 108 mg/kg body weight in 1964 (FAO/WHO, 1964) 
and 250 - 466 mg/kg in 1971 (FAO/WHO, 1971b). A major contributing 
factor, according to the latter report, was the presence of highly 
toxic pyrophosphates in earlier samples; it was implied that the 
impurities had been produced during storage and eliminated by 
stabilization (detail unspecified) of formulated material.  It 
seems likely that the pyrophosphate concerned in this improvement 
was monothiono-TEPP with an oral LD50 in mice of about 4 mg/kg body 
weight (Margot & Gysen, 1957).  Both the sulfotepp and monothiono-
TEPP content of an emulsifiable concentrate of diazinon and its 
toxicity increased rapidly when it was stored in tinned-steel 
containers instead of in inert-lined aluminium ones (Soliman et 
al., 1982).  However, in 1979, it was reported that sulfotepp was 
also present in many standard and formulated preparations of 
diazinon at concentrations ranging from 0.2 to 0.8% and that the 
percentage was unrelated to the age of the sample (Meier et al., 
1979).  It seems likely that this impurity was formed during the 
synthesis of diazinon using diethyl phosphorothiochloridate.  
Sulfotepp was 60 - 80 times more toxic than diazinon for the rat, 
so that at least one-third of the toxicity of typical diazinon 
might be attributed to the impurity.  This calculation is probably 
an underestimate, since it seems that metabolic disposal of an 
impurity is often slowed markedly by competition from the major 
component.  It can be said that there may be "reverse potentiation" 
of the toxicity of the impurity by the major component (diazinon). 

    Formation of pyrophosphates is implicit in the mode of 
synthesis of the many organophosphorus pesticides with a 
phosphorochloridate or phosphorothionochloridate as a precursor.  
TEPP or its methyl analogue would be unlikely to survive much 
aqueous washing during production, but the mixed mono- or disulfo 
analogues may well survive, unless deliberately eliminated.  It 
seems likely that sulfotepp is generally present in parathion 
(Diggory, 1977); however, since both the parent and the impurity 
have similar LD50s, pure and impure preparations do not differ 
significantly. It is a curious fact that the lower the true 
toxicity of a pesticide, the more marked may be the effect of an 
impurity in changing its toxicity.  It might be very rewarding 
both to analyse more thoroughly and to reexamine the toxicities of 
low-toxicity pesticides such as bromophos which is said to have an 
LD50 in various mammals of 3 - 8 g/kg body weight (FAO/WHO, 1973b); 
even this low toxicity might be attributable to the impurities 
rather than to the pure compound.  An analogous situation certainly 
pertains concerning the potentiation of malathion (see below).  Impurities potentiating the toxicity of the major 

    There does not appear to be any indication that the MFO status 
of animals is different after administration of technical grade 
organophosphorus insecticides compared with pure.  Alterations of 
the MFO status of animals because of diet, sex, drugs, etc., 
discussed in sections 6.3.2, 6.3.3, and 6.3.5, are unpredictable in 
their effect on the LD50.  In contrast, inhibition of the esteratic 
capacity of mammals increases the toxicity of pesticides that 
depend principally on tissue esterases in their metabolism (section 
4.3).  Malathion is a notable example of an organophosphorus 
pesticide in which the toxicity is enhanced when tissue esterases 
are inhibited.  Until comparatively recently, such inhibition was 
only known in situations where an unrelated organophosphorus ester 
was administered to test animals a short time before the malathion.  
However, it is now known that several impurities present in most 
samples of malathion prepared for use as pesticides, are capable of 
inhibiting tissue carboxylesterases.  Some of these impurities act 
very rapidly and so prevent the normal metabolism of malathion and 
potentiate its toxicity.  This enhanced toxicity has been expressed 
in man. Several hundred spray workers were intoxicated while 
spraying certain formulations of malathion in Pakistan, and 5 died 
(Baker et al., 1978).  Isomalathion and several trimethyl 
phosphorothiolates are found in most commercial preparations of 
malathion, but the levels depend markedly on the formulation and 
on storage conditions.  The potentiating power of small amounts of 
these impurities are shown in Table 8. Examination of samples of 
formulated malathion, known to be unusually toxic, showed a fair 
correlation of toxicity only with the percentage content of 
isomalathion (Aldridge et al., 1979; Miles et al., 1979).  However, 
the correlation was imperfect when a large number of samples were 
examined and the addition of known further amounts of pure 
isomalathion to the formulated samples caused more than the 
expected potentiation (Aldridge et al., 1979).  The authors 
concluded that, although isomalathion contributed the main effect, 
there was also significant potentiation by other agents present in 
the samples; the chief candidate was  O,S,S -phosphorodithioate. 

    Most unformulated samples of technical grade malathion seem to 
have an LD50 for rats in the range of 1500 - 2000 mg/kg body weight.  
Such material contains some potentiating impurities (Pellegrini & 
Santi, 1972; Umetsu et al., 1977), but has proved acceptable as a 
basis for formulated insecticides with little toxic hazard.  
However, it is now clear that some formulated samples increase 
markedly in both their impurity content and toxicity, when they are 
stored at elevated temperatures.  Not only are temperature and time 
important, but also the formulating agents (Table 9), and almost 
half of the malathion lost from Formulation C is apparently 
transformed to isomalathion with a massive potentiation, whereas 
the increase in toxicity is less marked in Formulations A and B, in 
which a much smaller proportion of lost malathion is converted to 

Table 8.  Potentiation of acute oral toxicity for rats by impurities
added to malathion
Compound            Amount   Potentiation   Purified    Reference
added               added    ratio found    malathion 
                    (%)                     used (LD50 
                                            mg/kg body 
isomalathion        0.4      3              10 700      Aldridge et al.
                    0.6      5                          (1979)
                    2        12
                    8        25
                    0.05     3              12 500      Umetsu et al.
                    0.1      4                          (1977)
                    0.5      6
                    2        10

 O,S,S -trimethyl    0.15     3              10 700      Aldridge et al.
phosphorodithioate  0.3      4                          (1979)
                    0.5      8
                    1.0      13
                    2.0      20
                    0.05     4              12 500      Umetsu et al.
                    0.2      6                          (1977)
                    0.5      7
                    0.035    2              8000        Pellegrini &
                    0.1      3                          Santi (1972)
                    0.2      4
                    0.5      7

 O,O,S -trimethyl    0.3      2              10 700      Aldridge et al.
phosphorothioate    1.3      4                          (1979)
                    0.2      3              12 500      Umetsu et al.
                    1        4                          (1977)
                    0.2      3              8000        Pellegrini &
                    0.5      4                          Santi (1972)

 O,O,S -trimethyl    1.5      2              10 700      Aldridge et al.
phosphorodithioate  5        5                          (1979)
                    1        4              12 500      Umetsu et al.
                    5        5                          (1977)
                    3.5      2              8000        Pellegrini &
                    4.5      3                          Santi (1972)

    There is much evidence that potentiation of malathion by 
extraneous compounds is associated with the inhibition of 
carboxylesterases.  Using malathion as specific substrate, Talcott 
et al. (1979b) showed that isomalathion and  O,S,S -trimethyl 
phosphorodithioate were potent inhibitors of rat liver and plasma 
malathion carboxylesterase,  in vitro and  in vivo; a partially-
purified sample of carboxylesterase from human liver was also 
sensitive to isomalathion (Talcott et al., 1979a). 

    The same hazard exists with impure samples of phenthoate as for 
malathion.  Pellegrini & Santi (1972) showed that technical samples 
containing 61 - 91% of the principal ester had LD50s (rat oral) of 
78 - 243 mg/kg body weight, while a purified preparation (98.5%) 
had an LD50 of 4700 mg/kg, though its toxicity for insects 
increased approximately in proportion to the purity.  The principal 
potentiating impurities were the  S -methyl isomer and the identical 
trimethyl phosphorothiolates found in malathion.  For phenthoate, 
as for malathion, the vulnerability to potentiation lies in the 
presence of the hydrolysable ethoxycarbonyl ester bond which, in 
pure samples, is the key to low mammalian toxicity. 

Table 9.  Effects of formulating agents and of storage 
time and temperature on composition and toxicity of 
malathion (50% wdp)a 
Storage conditions    Composition (%)           Oral LD50
Temperature  Time     Malathion   Isomalation   (rat)
(°C)         (days)
                       Formulation A

             0        48.0        0.38          2800
38           60       45.5        0.37          2230
             90       44.2        0.49          1740
55           6        47.6        0.30          2520
             13       46.4        0.37          1760
90           1        40.9        0.69          950

                       Formulation B

             0        48.8        0.18          2540
38           60       47.2        0.79          1130
             90       46.5        0.81          1330
55           6        45.2        0.67          1200
             13       43.6        0.55          1170
90           1        39.9        0.32          1900

                       Formulation C

             0        50.6        0.61          2660
38           90       44.9        3.7           590
55           6        46.2        3.4           535
             13       43.7        3.5           555
a   From: Miles et al. (1979).

    The presence of the  S -methyl isomer (0.32%) in a commercial 
fenitrothion formulation was shown by Miles et al. (1979).  The 
concentration increased to > 1% during accelerated storage tests, 
but there was no concomitant increase in the toxicity of the 
formulation.  This observation on a compound not heavily dependent 
on esterases for the primary step of detoxication, points to the 
need to consider biochemical mechanisms in assessing possible 
hazards.  There need be no general concern about the presence of 
small amounts of isomers in organophosphorus pesticides.  The 

presence of isoparathion in parathion is well-known, but there is 
no suggestion of any marked change in toxicity brought about by 
this impurity. 

    Some organophosphorus pesticides contain carboxylamide bonds 
rather than carboxyester.  These include dimethoate, dicrotophos, 
monocrotophos, phosphamidon, and acephate.  There appears to be 
little evidence that impurities in commercial formulations of any 
of the above pesticides markedly alter the toxicity, apart from a 
small (1.6x) decrease in the mammalian toxicity of acephate, after 
storage for 6 months at 40 °C; the insecticidal activity of the 
compound was unchanged (Umetsu et al., 1977).  During the storage 
period, the concentration of various impurities changed, but no 
relationship between these changes and altered toxicity was 

6.3.5  Effects of other pesticides and of drugs

    All organophosphorus and carbamate insecticides exert their 
acute toxic action by attack on the AChE.  Thus, it follows that 
exposure to more than one such pesticide will usually produce at 
least an additive effect.  Besides this simple effect, other 
pesticides or drugs may also influence the toxicity of an 
individual organophosphorus pesticide by interfering with its 
metabolism, activation, and disposal. 

    Not all organophosphorus pesticides and probably no carbamate 
pesticides inhibit tissue carboxylesterase to potentiate malathion 
in the manner discussed in section 6.3.4.  However, like all other 
enzymes, the carboxylesterases have their own structure-activity 
pattern: this has not been worked out in a systematic fashion.  It 
is clear that, with some compounds, profound inhibition of liver 
carboxylesterase can be achieved without inhibition of AChE 
sufficient to cause signs of poisoning.  This class includes many 
thioalkyl esters such as the trimethyl esters and also  S,S,S -tri- n 
-butyl phosphorotrithioate (DEF), which are potent potentiators of 
malathion toxicity via carboxylesterase inhibition. EPN is a 
phenylphosphorothioate insecticide that also acts in this way.  
Tables 10 and 11 show examples in which measurements of effects on 
tissue carboxylesterases and AChE are of value in predicting the 
potentiation of malathion toxicity (Murphy, 1969). 

Table 10.  Comparison of enzyme inhibition caused by 
several pesticidesa 
Insecticide  Dietary concentration (mg/kg) resulting in         
(period)             40 - 60% inhibition of:             
             Red cell-        Liver-         Plasma-
             cholinesterase   malathionase   malathionase
Parathion    3                5              5
(7 days)
Fenchlorphos 500              30             30
(7 days)
Malathion    500              100            500
(30 days)
a   From: Murphy (1969).

Table 11.  Effect of feeding fenchlorphos on  in vivo  
anticholinesterase activity of malathiona 
Fenchlorphos      Malathion        Inhibition of brain
concentration     challenge dose   AChE 1 h after 
in diet (mg/kg)   (mg/kg ip)       challenge (%) 
0                 200              13

30                0                1

30                200              61
a   From: Murphy (1969).

    Potentiation of the toxicity of organophosphate compounds for 
mammals not containing a carboxylester function, does not appear to 
be a significant hazard, though it is possible that potentiation of 
some carboxylamide pesticides by an analogous inhibition of tissue 
amidases may occur; certainly, EPN potentiates the toxicity of 
dimethoate (El-Sebae, 1980). Potentiation of the toxicity of 
organophosphorus pesticides for insects by inhibition of MFO 
activity is well-known, and many potent synergists are used in 
agriculture for this purpose (Wilkinson, 1971), but much less has 
been reported concerning similar effects in mammals.  This may 
reflect the greater versatility of mammals compared with insects in 
disposing of organophosphorus esters (section 4.3). Competition 
for one metabolic route within the animal often does not greatly 
alter its total capacity to deal with a foreign compound.  
Keplinger & Deichmann (1967) combined pairs of various pesticides 
in proportion to their oral LD50s, determined individually, and 
then measured the oral toxicity of the mixtures in rats or mice.  
They calculated a ratio of expected LD50/observed LD50 where 
"expected LD50" was the sum of half the LD50 value of each of the 2 
constituents. Their study included 7 chlorinated hydrocarbons, 
the carbamate carbaryl, and 5 organophosphates including diazinon, 
malathion, and parathion.  With a "no-effect" ratio of 1.0, they 
considered measured ratios greater than 1.75 or less than 0.57 as 
probably significant of real effects.  In a number of cases, less 
than additive effects were noted for combinations of a chlorinated 
hydrocarbon and an organophosphate, e.g., aldrin + diazinon (0.55), 
DDT + malathion (0.54), toxaphene + carbonylfenthion (0.54): this 
might well be expected if the mode of toxicity were different and 
metabolic pathways were not markedly altered. The only cases of 
potentiation involving organophosphates were also not surprising.  
A triple combination of parathion, malathion, and chlordane had a 
ratio of 1.99. This effect was probably due to simple potentiation 
of malathion by parathion, since chlordane alone did not potentiate 
either organophosphorus compound.  Mixtures of Aramite (sulfurous 
acid 2-chloroethyl 2-[4-(1-1-dimethylethyl)-phenoxyl-1-methylethyl 
ester) with several organophosphates in mice had ratios of 1.86 - 
2.14.  However, since the LD50 of Aramite in mice is high (2000 
mg/kg body weight), it may be that the 500 mg/kg administered in a 
mixture was absorbed more efficiently and was therefore more 
effective proportionately than the much higher LD50 dose of Aramite 

    As noted above, aldrin had little effect on the toxicity of 
organophosphorus insecticides, when administered at the same time.  
However, a number of chlorinated hydrocarbons (aldrin, DDT, 
chlordane, etc.) are well-known as stimulators of MFO activity in 
(principally) the mammalian liver.  This activity increased 
markedly during a period of a few days after dosage, and 
pretreatment of mice with aldrin (16 mg/kg body weight), 4 days 
before a challenge dose of 6 different organophosphates, markedly 
reduced (up to 5-fold) the toxicity of each (Murphy, 1969).  
Similar results were obtained with other classes of MFO inducers 
such as phenobarbital.  Murphy points out that the mechanism of 
these effects probably includes stimulation of liver 
carboxylesterase as well as MFO. 

    From the observations above, it appears that simple mixing of 
an organophosphorus insecticide with a chlorinated hydrocarbon is 
unlikely to adversely influence the acute toxicity for mammals, as 
expressed by LD50 value. However, administration of DDE at 55 
mg/kg diet to adult male Japanese quail led to an increasing 
susceptibility to challenge doses of parathion (2.5 mg/kg) 
administered orally; mortality in these birds increased from 0 to 
30% after 1 week of feeding and 60% after 3 weeks (Ludke, 1977). 

    The problem of potentiation by some organophosphates of the 
toxicity of pesticides containing carboxyl ester bonds may be 
significant.  This has been demonstrated for malathion in animals 
(section 6.3.4) and in man (section 7.1.3).  It may also be a 
problem for pyrethroid insecticides for most of which degradation 
by mammalian carboxyesterases is a significant detoxification 
pathway (Miyamoto, 1976). 

6.3.6  Species

    No clear ranking of species sensitivity to organophosphorus 
pesticides as a class can be given.  A general impression is that 
mice, hamsters, and guinea-pigs may be more sensitive than rats, 
with respect to a number of compounds, but the converse is seldom 
true.  However, most available data have been produced with little 
reference to conditions of husbandry, diet, hormonal status, etc., 
so that only very marked differences, which do not usually seem to 
exist, would emerge.  Birds tend to be more sensitive to 
organophosphorus pesticides (Schafer, 1972) and amphibians less 
sensitive than mammals.  It has been suggested, but not confirmed, 
that these differences might be due to differences in the activity 
of enzymes in species that hydrolyse organophosphorus compounds and 
thereby contribute to detoxification. 

    The toxicity of several organophosphorus pesticides for 
different species seems to be inversely related to the activity of 
the plasma A esterase, which degrades the pesticide oxon.  Such 
activity is considerably lower in birds than in mammals (Machin et 
al., 1978).  When 14 avian species were compared with 5 mammalian, 
the average plasma activity against pirimiphos-methyl oxon was 170 
times less, and that against paraoxon, at least 13 times less 
(Brealey et al., 1980). Differences in liver microsomal oxidative 

activity involved in the metabolism of several organophosphorus 
pesticides by mammals and birds were less profound, though fish 
liver was less active (Miyamoto & Ohkawa, 1978). 

    A multitude of factors contribute to the great difference 
between the oral toxicity of chlorofenvinphos for the rat (10 mg/kg 
body weight) and that for the dog (> 5000 mg/kg). These include 
efficiency of absorption, at least 2 metabolic detoxification 
processes, the rate of uptake by the brain, and a 7-fold difference 
in the sensitivity of the brain AChE to this compound in the 2 
species (Hutson & Hathway, 1967; Donninger, 1971). 

    Adult hens, cats, dogs, and larger farm animals are all 
susceptible to organophosphorus delayed neurotoxicants (Davis & 
Richardson, 1980; Johnson, 1982a).  There is no clear ranking of 
dose-sensitivity, though hens seem to be most uniformly responsive.  
The full clinical response is not easily seen in laboratory 
primates and rodents, though morphological damage may be detected 

6.3.7  Other factors

    The effects of solvents on chemical stability and isomerization 
reactions were noted in section 4.5.  The effects of formulation 
agents on stability and, therefore, on the toxicity of malathion 
have also been noted previously (section 6.3.4).  It is likely that 
percutaneous absorption will be greater for liquid formulations 
than for powders but that powders may adhere longer thereby 
enhancing an effect, if proper hygiene is not observed.  A number 
of examples are quoted by El-Sebae (1980), in which formulated 
pesticides were more toxic than the technical preparation (Table 
12).  In many cases, this is due to the fact that the solvent in 
the formulation facilitates the uptake of the pesticide into the 
body. The toxicity of other components of the formulation may play 
a role (especially in the case of pesticides of very low toxicity, 
such as tetrachlorvinphos) (Table 12), as well as potentiation.  
El-Sebae noted that, in some cases, the I50 for inhibition of ChEs 
 in vitro by these compounds differed.  This could be relevant in 
the case of the directly-active oxon-type pesticide tetrachlorvinphos, 
but in cases where the test was performed with a thioate, the 
anticholinesterase activity would depend almost entirely on trace 
oxon impurities, which are often destroyed rapidly  in vivo and 
contribute little to toxicity compared with the bulk of oxon 
produced metabolically. 

Table 12. Comparative toxicity for mice of 
some technical and formulated 
organophosphorus pesticidesa 
Pesticide            24-h oral LD50                    
                     (mg/kg body weight)
                     Technical   Formulated
phosfolanb            12          11

chlorpyriphos        140         60

leptophos            162         83

tetrachlorvinphos    5000        1800
a   From: El-Sebae (1980).
b   (diethoxyphosphinothioyl)dithioimidocarbonic 
   acid, cyclic ethylene ester.

6.4  Acquisition of Tolerance to Organophosphorus Insecticides

    This topic has been discussed in section 6.3.1, where it was 
noted that when AChE levels were reduced progressively over a 
number of days or weeks, animals showed cholinergic signs of 
poisoning which, in animals that survived, decreased in severity 
and sometimes disappeared completely, though ChE inhibition was 
maintained.  This phenomenon is separate from the fact that 
permanent inhibition of 30 - 50% is ineffective in producing 
measurable symptoms.  The basis for acquired tolerance is not fully 
known, though a "down regulation" in the muscarinic ACh receptor is 
thought to be a contributary cause.  This involves both reduced 
sensitivity and reduced numbers of receptors (Costa et al., 1982). 

6.5  Therapy of Experimental Organophosphorus Poisoning

    The understanding of the mechanism of acute toxicity of 
organophosphorus pesticides has provided the basis for rational 
therapy.  The effects of inhibition of AChE, as described in 
section 6.1.1, are common to all organophosphorus pesticides 
intoxications.  However, the speed of onset and the rate of unaided 
recovery from sub-lethal doses vary greatly, depending on the 
chemical nature of the pesticide, the route of exposure, and on 
whether this exposure was a sudden overwhelming dose or a drawn-
out process. 

    Factors leading to a slow onset of symptoms include:

     (a)  Slow absorption or metabolic activation: this is often 
          associated with extremely low solubility and therefore 
          with the presence of large hydrophobic groups in the 
          ester molecule; pesticides such as haloxon, chlorpyrifos, 
          and leptophos are of this type; 

     (b)  Persistence in the system of a comparatively stable 
          inhibitor of ChEs.  This could be as a low concentration 
          of an active inhibitor such as demeton- S -methyl 
          sulfoxide or high concentrations of a weak inhibitor such 
          as methamidophos. 

    Factors leading to rapid clearance of symptoms include:

     (a)  Rapid clearance of the pesticide and its active agents, 
          as with trichlorfon and dichlorvos; rapid clearance 
          occurs also with nerve agents such as soman and sarin, 
          which have been much used in studies on therapy in 
          experimental animals. 

     (b)  A slow rate of aging of inhibited AChE giving opportunity 
          for reactivation (spontaneous or induced) to occur; 
          diethyl phosphorylated AChE ages more slowly than 
          dimethyl or diisopropyl. 

    (c)   Rapid spontaneous reactivation of inhibited AChE, such as 
          occurs after inhibition by all dimethyl or bis-2-
          chloroethyl phosphates.  In this case, the possibility of 
          reinhibition by a persistent compound will affect the 

    The factors noted above, which influence speed of onset and 
remission of effects, influence the prognosis for response to 
therapy but do not markedly alter the nature of optimal treatment.  
Maximum benefit comes from combined treatment with an 
anticholinergic drug (usually atropine) plus a reactivator of 
inhibited ChE (an oxime) with diazepam, and also artificial 
respiration.  The effects of the components will be discussed 
individually below. 

6.5.1  Palliation

    Artificial respiration alone can be very effective in 
maintaining life, since the primary cause of death in 
organophosphorus poisoning is respiratory failure (section 6.1.1). 
Such treatment gains time for the processes, natural or imposed, 
that lead to the return of sufficient ChE activity to maintain 

6.5.2  Antagonism of effects of ACh

    Atropine antagonizes many of the peripheral muscarinic effects 
of excess ACh and also some central effects.  However, there was no 
correlation between the peripheral anticholinergic activity of a 
range of atropine-like drugs and their capacity when used alone (or 
in conjunction with oximes) (section 6.5.3) to protect against the 
lethal effects of sarin (Coleman et. al., 1962; Brimblecombe et. 
al., 1970). Moreover, the ranking of the therapeutic efficacy of 
atropine analogues varied according to the test species (rat, 
mouse, or guinea-pig), and all effects were small (protective ratio 
< 1.5) in mice and guinea-pigs, but much larger and more variable 
(1.2 - 9.3) in rats.  The ranking changed yet further when the drug 

was combined with oxime P2S (see below), though the protective 
ratio with some compounds rose to 18 - 24 in guinea-pigs, 9 - 80 in 
rats, but only 1.8 - 6.3 in mice.  These confusing effects are now 
thought to be at least partially due to an anticonvulsant effect 
contributed variously by the atropine analogues.  Anticonvulsants 
often supplement the effects of atropine or of combined 
atropine/oxime therapy (see below). In particular, diazepam 
(valium) is known both to raise the LD50 and speed recovery in some 
cases (Johnson & Wilcox, 1975).  These authors implied that the 
mechanism might be partly direct antagonism to some central effects 
of ACh and partly indirect.  When diazepam is included in the 
therapeutic package, there appears to be little evidence that 
alternative anticholinergic drugs to the well-proved atropine are 
superior (Green et al., 1977).  It has been reported that, in 
prophylaxis against the toxicity of DFP in mice, the protection 
factor was 28 when atropine and obidoxime were used but 180 when 
Dexetimide (a drug with strong central anticholinergic activity) 
was substituted for atropine.  The particular advantage claimed for 
this drug was that, in the therapy of rabbits intoxicated with up 
to 60 x LD50 of paraoxon or 80 x LD50 of DFP, one single 
intravenous injection of Dexetimide (8 - 16 mg/kg body weight) was 
effective in conjunction with obidoxime, whereas repeated doses of 
atropine were necessary (Bertram et al., 1977).  Dexetimide is used 
for the treatment of parkinsonism and is available commercially.  
However, Dexetimide has not been evaluated in conjunction with 
diazepam or compared with atropine plus diazepam, and no details 
were given of the hazards of its use and side-effects in control 

6.5.3  Reactivation of inhibited AChE

    As indicated in section 4.5.1, inhibited ChEs can be 
reactivated  in vitro by treatment with appropriate nucleophilic 
agents, of which salts of the oxime  N- methylpyridinium-2-aldoxime 
are the most commonly used (the chloride is known as pralidoxime 
and the methanesulfonate as P2S).  In some countries, obidoxime 
(ToxogoninR ), which is a bis-quaternary oxime, is recommended at 
slightly different doses than pralidoxime, but the mode of action 
is similar.  The scope for further improvement in the design of 
therapeutic oximes is discussed by Gray (1984). 

     In vivo, there are 2 limitations to the benefits to be 
obtained from the use of these agents: 

    (a)   Access

    The quaternary oximes are thought not to cross the blood-brain 
    barrier easily (Taylor, 1980).  However, some experimental 
    work, summarized by Lotti & Becker (1982b), suggests that there 
    may be limited access, and this may have a significant, albeit 
    small, effect in reversing inhibition of AChE to improve the 
    clinical state.  Other more direct beneficial action of the 
    oximes directly at synapses in the medullary respiratory centre 
    cannot be ruled out.  The prompt improvement in the level of 
    consciousness observed and in the EEG of an intoxicated child 

    when iv infusion of 2-PAM was commenced (Lotti & Becker, 1982b) 
    also seemed to indicate that there was some access to important 
    brain regions. It has been claimed that obidoxime (25 mg/kg 
    body weight) injected intraperitoneally in rats, 5 min after a 
    dose of armin, was effective in reactivating 33% of the 
    inhibited AChE of the ponto-medullary region, which contains 
    the centre for control of respiration (Vasic et al., 1977).  
    However, there were no controls appropriate to disprove the 
    alternative explanation that the oxime had altered the 
    circulating level of armin (by direct destructive interaction 
    or otherwise), which, although interesting, is unlikely to be 
    relevant to therapy instituted later after dosing, nor is such 
    destruction-protection unique to toxogonin. 

    (b)   Aging of inhibited AChE

    As noted in section 4.5.1, inhibited AChE is converted by a 
    time-dependent reaction to a form resistant to reactivators.  
    Thus, oxime therapy becomes less effective with time after 
    poisoning.  The rate of aging of dialkyl-phosphorylated AChE is 
    Me > IsoPr > Et (O'Brien, 1967), but little has been published 
    on the rate of aging when phosphonyl groups derived from 
    pesticides are attached to the enzyme.  When one or both of the 
    residual alkyl groups are attached to phosphorus through sulfur 
    rather than oxygen, the rates of both spontaneous reactivation 
    and of aging of inhibited bovine erythrocyte AChE are markedly 
    increased (Clothier et al., 1981).  Ethoprophos is one of the 
    newer pesticides that contain such a residual alkylthio group; 
    no published studies are known of therapy after poisoning with 
    this or related pesticides. 

6.5.4  Efficacy of therapy

    As reported above, the combination of atropine plus oxime is 
far more effective in most cases than the mere summed effects.  
This is because the peripheral neuromuscular junctions 
(particularly the diaphragm) and the sympathetic ganglia, where 
oximes reactivate AChE, are nicotinic and are unaffected by 
atropine, so that separate aspects of intoxication are treated by 
the two agents.  There is speculation that some oximes may exert a 
protective effect by acting as depolarizing agents at the 
neuromuscular junction.  This may also account for the slight 
therapeutic effects of some analogues of toxogonin which do not 
have any nucleophilic oxime group or reactivating power (Schoene & 
Oldiges, 1973). Diazepam, also, is ineffective, except in 
combination with atropine and oxime. 

    Persistence of the toxic agent may interfere with successful 
therapy.  Thus, single doses of atropine + oxime were of only 
marginal efficacy in altering the LD50 of isofenphos in rats 
(FAO/WHO, 1982b).  However, when therapeutic doses were given 
repeatedly at about 12-h intervals, for 2 - 3 days, the LD50 for 
rats was raised about 4-fold; for hens, the increase was 15-fold 
(Wilson et al., 1984).  It appears that the failure of one-shot 
therapy in this case was due to persistence of the toxic agent 

rather than to a different mode of intoxication or to formation of 
an inhibited form of AChE that resisted reactivation.  The same 
situation may pertain for profenofos intoxication, which appears 
not to respond well to therapy (El-Sebae, personal communication, 


7.1  Acute Cholinergic Poisoning

    The clinical picture of organophosphorus intoxication results 
from accumulation of ACh at nerve endings.  The syndrome is 
described in detail in several major references (Namba et al., 
1971; Kagan, 1977; Taylor, 1980; HMSO, 1983; Plestina, 1984).  The 
symptoms can be summarized in three groups as follows: 

    (a)   Muscarinic manifestations

     -   increased bronchial secretion, excessive sweating,
         salivation, and lachrymation;

     -   pinpoint pupils, bronchoconstriction, abdominal
         cramps (vomiting and diarrhoea); and

     -   bradycardia.

    (b)   Nicotinic manifestations

     -   fasciculation of fine muscles and, in more severe
         cases, of diaphragm and respiratory muscles; and

     -   tachycardia.

    (c)   Central nervous system manifestations

      -  headache, dizziness, restlessness, and anxiety;

     -   mental confusion, convulsions, and coma; and

     -   depression of the respiratory centre.

    All these symptoms can occur in different combinations and can 
vary in time of onset, sequence, and duration, depending on the 
chemical, dose, and route of exposure.  Mild poisoning might 
include muscarinic and nicotinic signs only.  Severe cases always 
show central nervous system involvement; the clinical picture is 
dominated by respiratory failure, sometimes leading to pulmonary 
oedema, due to the combination of the above-mentioned symptoms. 

    Clinical diagnosis is relatively easy and is based on:

    (a)  medical history and circumstances of exposure; and

    (b)  presence of several of the above-mentioned symptoms,
         in particular, bronchoconstriction and pinpoint
         pupils not reactive to the light.  Pulse rate is not
         of diagnostic value, because the AChE effects on the
         heart reflect the complex innervation of this organ.
         On the other hand, since changes in the conduction
         and excitability of the heart might be life-
         threatening, monitoring should be performed.

    Confirmation of diagnosis is made by measurement of AChE in RBC 
or plasma-pseudoChE, and, also, of the dibucaine number (to rule 
out genetic deficiencies). 

    Measurements of blood-ChE during therapy are also useful in 
assessing the treatment with oximes, though there might not be a 
correlation between the severity of symptoms and the degree of ChE 
inhibition: comparison should be made with pre-exposure levels, 
wherever possible. 

    Chemical analysis of body fluids (urine, blood, gastric lavage) 
should be made in order to identify the compounds that caused 

7.1.1  Methods for assessing absorption and effects of
organophosphorus insecticides

    As well as assessments of general health and behaviour, the 
study of the effects of this class of pesticides is favoured 
compared with that of some other classes since the basic 
biochemical mechanisms (inhibition of esterases) are known for the 
major toxic effects.  Biochemical and neuro-physiological 
techniques, relevant to the principal effects of all the compounds, 
have been established.  Identification of the monobasic acid type 
of urinary metabolite, which is commonly produced, is an indicator 
of exposure rather than of an effect, but it seems appropriate to 
outline the technique in this sub-section.  Wherever possible, test 
findings should be compared with pre-exposure measurements on the 
same individual.  Analysis of urine as a means of monitoring exposed

    As previously discussed in section 4, organophosphorus 
pesticides may undergo hydrolysis  in vivo to yield substituted 
phosphoric acids that are subsequently excreted in urine. Advances 
in gas chromatography and combined gas chromatography/mass 
spectrometry (CG/MS) have made it possible to analyse the urine of 
exposed persons for the presence of appropriate metabolites.  It is 
usually necessary to preserve the sample by the addition of 
chloroform, to concentrate or extract the metabolite(s), and to 
convert them to suitably-volatile derivatives that can be detected 
by GC.  Obviously, access to a well-equipped analytical laboratory, 
capable of the quick processing of samples, is a necessary factor 
if monitoring by urine analysis is proposed.  However, in some 
cases, simpler and sensitive colorimetric tests are available for 
screening the urine of exposed persons.  Thus, 4-nitrophenol can 
be measured directly in the urine of workers exposed to parathion 
(Wolfe et al., 1970). 

    Consideration of the concentration of metabolite(s) in the 
urine can be helpful in determining patterns of exposure, and these 
concentrations can be calibrated against the effects on AChE for a 
particular pesticide.  However, the time-course and peak of 
excretion of metabolites appears to vary according to dose (Bradway 
et al., 1977), so that serial sampling and analyses of urine are 
desirable.  Levels of metabolite alone cannot be considered a guide 

to hazard.  This is obvious when it is realized that pesticides 
that have very different toxicities may yield identical acidic 
metabolites.  Thus, the level of metabolites in urine, after 
exposure to sufficient amounts of the very toxic parathion-methyl 
to depress blood-AChE to 50%, will be much lower than that of the 
identical metabolites, following exposure to the related 
fenitrothion, which is about 40 times less toxic.  Biochemical methods for the measurement of effects

    AChE is present in human erythrocytes (RBC) and is the same as 
the enzyme present in the target synapses.  Thus, levels of AChE in 
RBC are assumed to mirror the effects in the target organs.  
However, it must be borne in mind that this assumption is only 
correct when the organophosphate has equal access to blood and 
synapses.  In the case of acute poisoning, a high inhibition of 
RBC-AChE is pathognomonic, but, in the follow-up of the 
intoxication, it might not be correlated with the severity of 
symptoms.  In the case of repeated exposures, additional 
difficulties in interpretation arise from possible development of 
tolerance.  However, monitoring of pre- and post-exposure levels of 
AChE in RBC gives a good measure of the effects of an exposure 
(Kaloyanova, 1975).  In cases where the pre-exposure AChE level is 
not known (as in accidental poisoning), reference can be made to a 
mean population AChE activity.  Blood-plasma contains a related 
enzyme called ChE or pseudoChE, which contributes to the whole-
blood enzymatic activity; the contribution of plasma-ChE in assays 
of AChE will depend on the type and concentration of the substrate 
used.  PseudoChE has no known physiological function and can be 
inhibited selectively by some compounds without causing a toxic 
response.  The sensitivities of AChE and ChE to inhibitors differ, 
so that measurements of the ability of whole-blood samples to 
hydrolyse the usual analytical substrates give only an approximate 
estimate of the activity of the erythrocyte-AChE.  However, under 
many kinds of field conditions, procedures using whole blood, are 
more practical than those using separated erythrocytes.  Quite 
commonly, pseudoChE is more sensitive to inhibitors. Thus, if 
separation of plasma and erythrocytes is possible, prior to assay, 
an indication of exposure can be obtained by assay of pseudoChE 
only.  Examples of selected organophosphorus insecticides, arranged 
according to their ability to inhibit preferentially either plasma 
or red cell-ChE in man, are given in Table 13 (Hayes, 1982). 

Table 13. Selected organophosphorus insecticides arranged 
according to their ability to inhibit either plasma- or 
red cell-cholinesterase in mana 
Plasma enzyme more inhibited   RBC enzyme more inhibited
Chlorpyrifos                   Dimefox
Demeton                        Mevinphos
Diazinon                       Parathion
dichlorvos                     Parathion-methyl
a     Modified from: Hayes (1982).

    ChE assay procedures vary greatly in sophistication, but the 
most satisfactory is that based on the procedure of Ellman et al. 
(1961).  A field method and kit for whole blood- and plasma-ChE 
determination have been developed (WHO, 1984b). Quick methods exist 
for the determination of ChE in serum using paper tests (Izmirova, 
1980) and for the colorimetric determination of ChE in whole blood 
(Tintometer): these may be useful in the differential diagnosis of 
organophosphate poisoning.  Interpretation of the test results is 
discussed in section 7.1.2. 

    The potential for delayed neuropathic response to an 
organophosphorus ester can be predicted by the assay of the 
esteratic activity of the target protein (NTE), in autopsy brain 
samples from dosed adult hens (section 6.1.2).  It has been shown 
(Dudek et al., 1979; Richardson & Dudek, 1983) that a low level of 
similar enzyme activity resides in lymphocytes and that there may 
be correlations under some circumstances between neurotoxic dose 
and available lymphocyte enzyme activity. The possibility of 
monitoring exposed individuals by means of human lymphocyte or 
platelet NTE activity is being explored (Lotti et al., 1983; 
Bertocin et al., 1985; Maroni & Bleeker, 1986).  Electrophysiological methods for the study of effects

    Electromyographic (EMG) studies using non-invasive surface 
electrodes have been claimed to give sensitive indications of 
exposure to organophosphorus pesticides, even in situations where 
blood-ChE activity has returned to normal levels (Jager et al., 
1970; Roberts, 1976).  The method requires electro-physiological 
equipment and a very skilled practitioner. There is still 
considerable doubt about the validity of some published studies.  
Reproducibility is known to be very sensitive to local factors such 
as temperature of the skin, and conflicting results have been 
published, some of which show small increases and some, small 
decreases in the ampli-tude of evoked muscle action potential, in 
response to nerve stimulation.  These findings have been reviewed 
by LeQuesne & Maxwell (1981), who noted that changes that have been 
reported tended not to be dose-related.  In addition, they 
evaluated the technique under controlled circumstances.  In a 
treatment to eradicate parasitic schistosomes, 55 children were 
dosed orally with trichlorfon, 3 times, at 2-weekly intervals, at 
doses that measurably depressed blood-ChE (mean 50%), but were not 
enough to cause overt toxic effects, apart from mild cramps and 
diarrhoea in a few cases.  Only 3 children showed a significant 
alteration in electromyographic response.  Shortly after the last 
(and highest) dose of 10 mg/kg body weight, 3 children developed 
repetitive activity recorded over the thenar muscles following 
supramaximal stimulation of the median nerve at the wrist.  The 
activity consisted of a small potential at the end of the main 
muscle response and was characterized by being abolished by a 
second stimulus 30 or 80 milliseconds after the first, or by 
maximum voluntary contraction for 10 seconds; the amplitude of the 
response to the second stimulus was not reduced.  These 
characteristics are necessary criteria that distinguish (these) 
dose-related responses from pre-existing natural (and 
idiosyncratic) responses, which can otherwise confuse EMG studies 

in a population.  Changes in amplitude measured on 52 control 
subjects (mean 13.8 ħ 2.5 SD), on 2 occasions (2 weeks apart), 
ranged from +5 to -3 mV.  Thus, EMG does not appear to give a 
highly sensitive measure of exposure to an ingested 
organophosphorus compound. 

7.1.2  Monitoring studies

    Measurement of whole blood-AChE is the most widely adopted 
method for monitoring the effects of occupational exposure to 
organophosphorus insecticides.  Physiological variations in blood-
ChE levels occur in a healthy person and are seen among a 
population.  It has been estimated that the coefficient of 
variation for AChE activity in samples from an individual is 8 - 
11%, and that a decrease of 23% below pre-exposure level may, 
therefore, be considered significant.  If the average of several 
pre-exposure values were available, then a decrease of 17% would be 
significant.  It has been recommended that, if measured activity is 
reduced by 30% or more of the pre-exposure value, AChE measurements 
should be repeated at appropriate intervals to confirm the results.  
Depressions of AChE or ChE in excess of 20 - 25% are considered 
diagnostic of exposure but not, necessarily, indicative of hazard. 
Depressions of 30 - 50% or more are considered indicators for 
removal of an exposed individual from further contact with 
pesticides until levels return to normal.  Work procedures and 
hygiene should also be checked (Zielhuis, 1972; WHO, 1975; CEC, 
1977; Kaloyanova et al., 1979; Plestina, 1984). 

    Urinary metabolites have been monitored as a means of comparing 
the efficiency of absorption of a pesticide by different routes. 

    The reports of the annual Joint FAO/WHO Working Parties, 
mentioned previously, contain summaries of numerous controlled 
exposure studies.  No cases appear to be known of significant 
clinical effects in man in the absence of depression of plasma- or 
erythrocyte-ChE levels.  No-observed-adverse-effect levels have 
been calculated on this basis, where the data are available, or 
have been estimated for man by extrapolation of the available data 
for exposed animals. 

7.1.3  Retrospective studies of populations exposed to 
organophosphorus pesticides: acute and long-term exposure

    Many thousands of cases of acute poisoning by organophosphorus 
pesticides have been recorded (Namba et al., 1971). The majority 
have been due to parathion and methyl parathion. Thus, Namba (1974) 
in a discussion of the relative toxicities of parathion and 
malathion, quoting Japanese Government statistics for the 7 years 
1958-62, 1966, and 1967, stated that there were 3311 accidental or 
occupational poisonings due to parathion including 188 deaths, 
while for malathion, the numbers were 63 and 10, respectively.  He 
noted that the difference was not due to the restricted use of 

    In the context of this general introduction, no descriptions 
and breakdown will be given of retrospective studies of populations 

exposed to organophosphorus pesticides. Such figures are relevant 
to individual substances and will be given in the appropriate 
Environmental Health Criteria. 

    It is generally thought that the only long-term effects 
attributable to overt or subclinical acute intoxication with 
organophosphorus compounds, or to prolonged low-level exposure, 
are behavioural (rather doubtful), and delayed-onset neuropathy in 
the case of certain compounds; these are dealt with in section 7.2. 

>7.2  Other Effects on the Nervous and Neuromuscular System Due to 
Acute or Long-Term Exposure

7.2.1  Delayed neuropathic effects

    The characteristics of this disorder are given in section 
6.1.2.  The agents most commonly causing delayed neuropathy in man 
are triaryl phosphate esters used in, e.g., hydraulic fluids; these 
do not have any AChE activity and are not pesticides.  In Table 14, 
organophosphorus pesticides are listed for which there is 
reasonable evidence that they have caused delayed neuropathy in 

Table 14.  Organophosphorus pesticides reported to cause 
delayed neuropathy in man
Pesticide          Number      Reference
                   of cases
mipafox            2           Bidstrup et al. (1953)

leptophos          8           Xintaras et al. (1978);
                               FAO/WHO (1979b)
methamidophos      9           Senanayake & Johnson

trichlorphon       many        Shiraishi et al. (1977);
                               Hierons & Johnson (1978);
                               Johnson (1981a)

trichlornat        2           Jedrzejowska et al.
                               (1980); Willems (1981)

EPN                3a           Xintaras & Burg (1980)

Chlorpyrifos       1           Lotti & Moretto (1986)
a     Moderate effects only and possibly other 
     etiological factors.

    The cases with mipafox involved a single occupational exposure 
to a compound that was developed before delayed neuropathy was a 
recognized hazard.  The cases with EPN and leptophos arose through 
repeated occupational exposure with inadequate precautions.  
Apparently cholinergic effects were often experienced, but not at 

the level of severe poisoning. A few cases with methamidophos and 
trichlorfon involved substantial occupational exposure, which 
caused severe acute poisoning prior to the development of 
neuropathy, but the majority of cases involved accidental or 
deliberate ingestion of quantities that might well have been fatal 
but for medical intervention.  The fact that most of the cases 
listed are due to exposure to phosphonates or phosphoramidates is 
in line with the structure-activity relationships listed in section 

    The value of measuring the neuropathy target esterase of human 
lymphocytes as a predictive monitor was proposed by Dudek et al. 
(1979) and Richardson & Dudek (1983).  Lotti et al. (1983) reported 
occupationally related changes in the lymphocyte NTE in spraymen 
during seasonal spraying of DEF, but overt neuropathy was absent.  
In a case of self-poisoning by a mixture of pesticides including 
chlorpyrifos (about 20 g diluted in petroleum distillates), 
Osterloh et al. (1983) noted that signs of cholinergic poisoning 
were limited and they attributed death to the effects of 
chlorophenoxyacetic acids.  Brain esterases were not inhibited at 
autopsy, but erythrocyte and peripheral nerve AChE levels were 
about 22% of normal and nerve NTE was about 30%.  This substantial 
inhibition of NTE suggested that treated survivors of severe 
poisoning by chlorpyrifos might well develop delayed neuropathy.  
This prediction was confirmed in a recent case of self-intoxication 
with chlorpyrifos (estimated dose 300 mg/kg body weight) in which 
very low levels of lymphocyte-NTE were found, 30 days after 
intoxication and after recovery from very severe cholinergic 
effects.  Typical moderate polyneuropathy developed in the 
following days (Lotti & Moretto, 1985). 

    Allegations have been made against a few other organophosphorus 
insecticides including malathion, omethoate, and parathion, though 
many accidental and intentional poisonings by these agents have not 
had any neuropathic sequelae. Experimental evidence against a 
neuropathic potential in these compounds is strong (section 6.1.2).  
However, in view of the serious paralytic effects involved, the 
evidence adducing that these pesticides were the causal agents is 
reviewed below. 

    (a)   Malathion

    Two alleged cases can be discounted.  Petry (1958) reported a 
case in which a physician contaminated himself frequently with 
chlorinated hydrocarbon pesticides during day-long gardening 
activities, about once per week, over a 10-year period.  In 1954, 
he commenced using 6% malathion in a "hose-on" device for garden 
pest control and, in 1955, he commenced using 50% malathion in a 
hand spray, both indoors and outside.  He soon developed signs of 
chronic anticholinesterase poisoning (generalized weakness and 
tremor, irritability, difficulty in focusing).  He eventually 
collapsed and his general condition improved in hospital.  However, 
he continued to experience generalized weakness and particular 
weakness in the right shoulder girdle, right serratus anterior, and 
both peroneal muscle groups, and these symptoms persisted to some 
extent for over a year.  The distribution of these symptoms of 

deficient muscle performance is quite atypical for delayed 
neuropathy and seems more likely to be due to prolonged moderate 
cholinergic insult from malathion precipitating weakness, anorexia, 
and weight loss, which then precipitated further ill-health as 
previously-stored chlorinated hydrocarbons was mobilized from 
degraded fat stores. DDT at 23 mg/kg plus a high level of organic 
chloride were found in a subcutaneous fat biopsy.  A muscle-
necrotising effect, due to prolonged cholinergic stimulation, as 
described in section 6.2.6, is also possible. 

    A separate case report of ascending paralysis following 
malathion intoxication (Healy, 1959) concerned an 18-month-old 
child exposed daily for 6 weeks to malathion from a garden spray.  
Contamination was dermal and also by inhalation and ingestion, 
leading ultimately to a cholinergic crisis and a prolonged period 
of weakness including extensive flaccid paralysis for several days.  
The condition responded to atropine and rest within 4 weeks.  In 
spite of the author's conclusion that this was a "demyelinating" 
(i.e., delayed neuropathic) disorder, the picture is typical of 
prolonged cholinergic insult responding to atropine and the 
comparatively slow clearance of accumulated pesticide with 
recovery from excessive nerve-muscle stimulation. 

    (b)   Omethoate

    A typical delayed neuropathy followed ingestion of an 
organophosphorus pesticide with suicidal intent (Curtes et al., 
1979).  Identification of the actual pesticide ingested was 
doubtful depending on a later hearsay report concerning a bottle in 
a garden shed, the contents of which were not analysed.  Lotti et 
al. (1981) assayed both the AChE and the NTE activities in 
autopsied brain after a fatal intoxication with omethoate and found 
that, even at the fatal dose, the NTE levels were normal while the 
AChE activity was highly inhibited.  Considering this data together 
with evidence of similar non-inhibition in experimental hens at up 
to 8 x the unprotected LD50, the authors concluded that, though the 
neuropathy was typical, it was likely that the toxic agent was some 
other organophosphorus compound more liable to cause neuropathy, 
such as trichlorfon or trichlornat (Table 13). 

    (c)   Parathion

    Only two cases of permanent incapacity have been attributed to 
parathion, though thousands of parathion poisonings are known (see 
earlier).  Petry (1951) attributed a case of neuropathy to the 
aftermath of several occupational incidents of cholinergic 
poisoning, but the history is entirely atypical in that symptoms 
developed only 4 months, rather than 2 - 4 weeks, after the last 
exposure.  Causation by parathion is therefore very unlikely. A 
farmer deliberately ingested parathion at a dose estimated to be at 
least 150 g (perhaps 500 x the estimated human lethal dose) in 600 
ml of methanol.  Vigorous therapy preserved his life, though he 
remained in a deep coma for 7 weeks.  On recovery from this 
experience, he was found to be suffering from flaccid paralysis of 
both legs and weakness of both hands with muscle atrophy (De Jager 
et al., 1981; 1982); partial recovery occurred during one year.  

Lotti & Becker (1982b) have discussed the complicating factors of 
the potentially supra-lethal dose of methanol and of the long coma.  
However, the clinical picture is not unlike a true moderate 
organophosphorus-induced neuropathy.  At such a colossal dose, the 
possibility of ingesting a significant amount of a neuropathic 
impurity in the parathion must be recognized.  This could be ethyl 
bis-(4-nitrophenyl) phosphorothioate; small but significant 
amounts of the appropriate oxon are present in some samples of 
paraoxon made from diethyl phosphorochloridate (Johnson, 1982b), 
and this oxon is a potent inhibitor of NTE. 

    (d)   Other organophosphorus pesticides

    Besides the atypical case attributed to malathion, Petry (1958) 
described another case in which symptoms persisted after a 
cholinergic crisis that followed severe intermittent exposures over 
3 seasons to a variety of insecticides including parathion, EPN, 
DDT, dieldrin, and lead arsenate. Some of the persistent symptoms 
might be compatible with a mild peripheral neuropathy.  Among the 
agents used, lead arsenate and dieldrin would be expected to 
contribute damage to the nervous system and EPN at about the LD50 
level causes neuropathy in hens and man (Tables 4, 13). 

    A case of slow-onset profound weakness with complete recovery 
within 3 months following contamination of an agricultural worker 
with the cotton defoliant, merphos ( S,S,S -tri- n -butyl 
phosphorothioite), was thought by the author to be of the delayed 
neuropathy type (Fisher, 1977). However, the clinical picture 
showed signs that are not seen in acute organophosphate 
intoxication (influenza-like onset of the syndrome and high level 
of protein in the spinal fluid). These signs are, however, 
characteristic of a Guillan-Barré syndrome, which might have been 
coincidental to the merphos exposure only 4 days previously.  It is 
possible that, later, a mild organophosphorus neuropathic effect 
was superimposed on the Guillan-Barré effect, since merphos can 
produce neuropathy in experimental animals (Johnson, 1970, 1975b).  
Recovery from very mild neuropathies is usually complete. 

7.2.2  Behavioural effects

    Although many epidemiological studies have been carried out, 
few controlled studies on man have been reported.  It is generally 
recognized that there are behavioural and psychic changes during 
overt clinical poisoning by organophosphorus insecticides and that 
these may take several months to regress (Karczmar, 1984).  
However, there is no information to suggest that effects occur at 
exposure levels that do not either alter ChE levels or produce 
physical symptoms.  Levin & Rodnitsky (1976) have reviewed the 
literature, including their own work, on different aspects of 
behaviour as affected by organophosphates.  Much was based on 
generalized complaints from workers occupationally exposed to many 
agricultural chemicals (and probably also to automobile fuels and 
lubricants and to alcohol).  In summary, they found that, in human 
subjects sufficiently exposed to organophosphates to depress 
plasma- or erythrocyte-ChEs, some or all of the following 

behavioural variables might be impaired.  In cognition: vigilance, 
information processing and psychomotor speed, and memory; in 
speech: both performance and perception; in psychic state: 
increased tendencies to depression, anxiety, and irritability; and 
in EEG records: a tendency to faster frequencies and higher 
voltages.  They also concluded that the EEG abnormalities were 
positively related to the level of AChE inhibition during the 
initial stages of inhibition.  Concerning studies on asymptomatic 
workers at risk from repeated exposure to organophosphorus 
pesticides, they considered that the evidence was equivocal for the 
presence of less severe or latent forms of any behavioural 
abnormalities.  However, Duffy & Burchfield (1980) claimed that 
changes in the EEG of individuals accidentally exposed to the 
nerve-agent sarin could be detected twelve months after the 
exposure.  This study was a sequel to the study on monkeys 
described in section 6.1.2, and the analyses of EEGs was performed 
as noted there.  They claimed significant differences (very small 
differences analysed by complex statistical procedures) between the 
group of sarin-exposed workers and controls, particularly in the 
region of beta-rhythm (but the comment on the spread among normal 
monkeys should be noted).  However, the authors were unable to pick 
out sarin-exposed individuals on the basis of the EEG. They also 
found (small) increased amounts of REM-sleep in the exposed 
workers.  Without controlled exposure and serial monitoring of 
effects in individuals, little can be deduced from these apparent 
marginal changes. 

7.3  Effects on Other Organs and Systems

    Very few effects, other than those described in sections 7.1 
and 7.2, have been noted, except those arising from ill health due 
to severe anticholinesterase effects. 

    Several adverse effects attributed to only one organophosphorus 
ester will be listed under the individual substances. 

7.4  Treatment of Organophosphate Insecticide Poisoning in Man

    All cases of organophosphorus poisoning should be dealt with as 
an emergency and the patient sent to hospital as quickly as 
possible.  Although symptoms may develop rapidly, delay in onset or 
a steady increase in severity may be seen up to 48 h after 
ingestion of some formulated organophosphorus insecticides. 

    Extensive descriptions of treatment of poisoning by 
organophosphorus insecticides are given in several major references 
(Kagan 1977; Taylor 1980; HMSO, 1983; Plestina 1984) and will also 
be included in the IPCS Health and Safety Guides to be prepared for 
selected organophosphorus insecticides. 

    The treatment is based on:

    (a)  minimizing the absorption;

    (b)  general supportive treatment; and

    (c)  specific pharmacological treatment.

7.4.1  Minimizing the absorption

    When dermal exposure occurs, decontamination procedures include 
removal of contaminated clothes and washing of the skin with 
alkaline soap or with a sodium bicarbonate solution. Particular 
care should be taken in cleaning the skin area where venupuncture 
is performed.  Blood might be contaminated with direct-acting 
organophosphorus esters, and, therefore, inaccurate measures of ChE 
inhibition might result.  Extensive eye irrigation with water or 
saline should also be performed. In the case of ingestion, vomiting 
might be induced, if the patient is conscious, by the 
administration of ipecacuanha syrup (10 - 30 ml) followed by 200 ml 
water.  This treatment is, however, contraindicated in the case of 
pesticides dissolved in hydrocarbon solvents.  Gastric lavage (with 
addition of bicarbonate solution or activated charcoal) can also be 
performed, particularly in unconscious patients, taking care to 
prevent aspiration of fluids into the lungs (i.e., only after a 
tracheal tube has been placed). 

    The volume of fluid introduced into the stomach should be 
recorded and samples of gastric lavage frozen and stored for 
subsequent chemical analysis.  If the formulation of the pesticide 
involved is available, it should also be stored for further 
analysis (i.e., detection of toxicologically relevant impurities).  
A purge to remove the ingested compound can be administered. 

7.4.2  General supportive treatment

    Artificial respiration (via a tracheal tube) should be started 
at the first sign of respiratory failure and maintained for as 
long as necessary. 

    Cautious administration of fluids is advised, as well as 
general supportive and symptomatic pharmacological treatment and 
absolute rest. 

7.4.3  Specific pharmacological treatment  Atropine

    Atropine should be given, beginning with 2 mg iv and given at 
15 to 30-min intervals.  The dose and the frequency of atropine 
treatment varies from case to case, but should maintain the 
patient fully atropinized (dilated pupils, dry mouth, skin 
flushing, etc.).  Continuous infusion of atropine may be necessary 
in extreme cases and total daily doses up to several hundred mg may 
be necessary during the first few days of treatment.  Oxime reactivators

    Cholinesterase reactivators (e.g., pralidoxime, obidoxime) 
specifically restore AChE activity inhibited by organophosphates.  
This is not the case with enzymes inhibited by carbamates.  The 
treatment should begin as soon as possible, because oximes are not 

effective on "aged" phosphorylated ChEs (section 6.5.3).  However, 
if absorption, distribution, and metabolism are thought to be 
delayed for any reasons, oximes can be administered for several 
days after intoxication. Effective treatment with oximes reduces 
the required dose of atropine.  Pralidoxime is the most widely 
available oxime.  A dose of 1 g pralidoxime can be given either im 
or iv and repeated 2 - 3 times per day or, in extreme cases, more 
often.  If possible, blood samples should be taken for AChE 
determinations before and during treatment.  Skin should be 
carefully cleansed before sampling.  Results of the assays should 
influence the decision whether to continue oxime therapy after the 
first 2 days. 

    The possible beneficial effects of oxime therapy on CNS-derived 
symptoms is discussed in section 6.5.3.  Diazepam

    Diazepam should be included in the therapy of all but the 
mildest cases.  Besides relieving anxiety, it appears to counteract 
some aspects of CNS-derived symptoms, which are not affected by 
atropine.  Doses of 10 mg sc or iv are appropriate and may be 
repeated as required (Vale & Scott, 1974).  Other centrally acting 
drugs and drugs that may depress respiration are not recommended in 
the absence of artificial respiration procedures.  Notes on the recommended treatment

    (a)   Effects of atropine and oxime

    The combined effect far exceeds the benefit of either drug 

    (b)   Response to atropine

    The response of the eye pupil may be unreliable in cases of 
organophosphorus poisoning.  A flushed skin and drying of 
secretions are the best guide to the effectiveness of 
atropinisation.  Although repeated dosing may well be necessary, 
excessive doses at any one time may cause toxic side-effects. 
Pulse-rate should not exceed 120/min. 

    (c)   Persistence of treatment

    Some organophosphorus pesticides are very lipophilic and may be 
taken into, and then released from, fat depots over a period of 
many days.  It is therefore quite incorrect to abandon oxime 
treatment after 1 - 2 days on the supposition that all inhibited 
enzyme will be aged.  Ecobichon et al. (1977) noted prompt 
improvement in both condition and blood-ChEs in response to 
pralidoxime given on the 11th - 15th days after major symptoms of 
poisoning appeared due to extended exposure to fenitrothion (a 
dimethyl phosphate with a short half-life for aging of inhibited 

    (d)   Dosage of atropine and oxime

    The recommended doses above pertain to exposures, usual for an 
occupational setting, but, in the case of very severe exposure or 
massive ingestion (accidental or deliberate), the therapeutic doses 
may be extended considerably.  Warriner et al. (1977) reported the 
case of a patient who drank a large quantity of dicrotophos, in 
error, while drunk.  Therapeutic dosages were progressively 
increased up to 6 mg atropine iv every 15 min together with 
continuous iv infusion of pralidoxime chloride at 0.5 g/h for 72 h, 
from days 3 to 6 after intoxication.  After considerable 
improvement, the patient relapsed and further aggressive therapy 
was given at a declining rate from days 10 to 16 (atropine) and to 
day 23 (oxime), respectively.  In total, 92 g of pralidoxime 
chloride and 3912 mg of atropine were given and the patient was 
discharged on the thirty-third day with no apparent sequelae. 


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Annex I.  Names and structures of selected organophosphorus pesticides
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS       
             other                              formula               molecular  Registry  
             name                                                     mass       number    
acephate     Orthene      phosphoramidothioic   C4 H10 NO3 PS            183.18     30560-19-1
             Ortran       acid, acetyl-,  O,S-                                              
                          dimetyl ester                                                    
Chemical Structure
amidithion   Thiocron     phosphorodithioic     C7 H16 NO4 PS2            273.33     919-76-6  
                          acid,  O,O -dimethyl                                              
                           S -[2-[(2-methoxy-                                               

Chemical Structure
amiton       Citram       phosphorothioic       C10 H24 NO3 PS           269.38     78-53-5   
             Inferno      acid,  S -[2-(diethyl-                                            
             Metramac     amino)ethyl]  O,O -di-                                            
             Tetram       ethyl ester                                                      

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
azinophos-   Cotnion-     phosphorodithioic     C12 H16 N3 O3 PS2          345.4      2642-71-9 
 ethyl       ethyl        acid,  O,O -diethyl-                                              
             Gusathion     S -[[4-oxo-1,2-benzo-                                            
             Ethyl,       triazin-3(4H)-yl]                                                
             Guthion      methyl] ester                                                    

Chemical Structure
azinophos-   Cotnion-     phosphorodithiotic    C10 H12 N3 O3 PS2          317.34     86-50-0   
 methyl      methyl       acid,  O,O -dimethyl-                                             
             gusathion     S -[[4-oxo-1,2,3-                                                
             guthion      benzotriazin-3(4H)-                                              
             metiltr-     yl]methyl] ester                                                 

Chemical Structure
azothoate    alamos       phosphorothiotic      C14 H14 ClN2 O3 PS        356.78     5834-96-8 
                          acid,  O -[4-[(4-                                                 
                          phenyl]  O,O -dimethyl                                            

Chemical Structure

Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
bromophos    netal        phosphorothioic       C8 H8 BrCl2 O3 PS         366.0      2104-96-3                         
             nexion       acid,  O -(4-bromo-                                                                       
                           O,O -dimethyl ester                                                                      

Chemical Structure

bromophos-   nexagan      phosphorothioic       C10 H12 BrCl2 O3 PS       394.06     4824-78-6                         
 ethyl                    acid,  O -(4-bromo-                                                                       
                           O,O -diethyl ester                                                                       

Chemical Structure

butonate     tribufon     butanoic acid,        C8 H14 Cl3 O5 P           327.54     126-22-7                          
                          nyl) ethyl ester                                                                         

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
chlorfen-    birlane      phosphoric acid,      C12 H14 Cl3 O4 P          359.58     2701-86-2                         
 vinphos     sapecron     2-chloro-1-(2,4-                                                                         
             supona       dichlorophenyl)                                                                          
                          ethenyl dimethyl                                                                         

Chemical Structure
chlorpyri-   dursban      phosphorothioic       C9 H11 Cl3 NO3 PS         350.59     2921-88-2                         
 fos         lorsban      acid,  O,O -diethyl                                                                       
                           O -(3,5,6-trichloro-                                                                     
                          2-pyridinyl) ester                                                                       

Chemical Structure
chlorpyri-   fospirate    phosphorothioic       C7 H7 Cl3 NO3 PS          322.53     5598-13-0                         
 fos         reldan       acid,  O,O -dimethyl                                                                      
 methyl      zertell       O -(33,5,6-trichloro-                                                                    
                          2-pyridinyl) ester                                                                       

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
coumaphos    agridip      phosphorothioic       C14 H16 Cl05 PS          326.78     56-72-4                           
             asunthol     acid,  O -(3-chloro-                                                                      
             co-ral       4-methyl-2-oxo-2H-                                                                       
             meldane      1-benzopyran-7-yl)                                                                       
             muscatox      O,O -diethyl ester                                                                       

Chemical Structure
crotoxy-     ciodrin      2-butenoic acid,      C14 H19 O6 P             314.3      7700-17-6                         
 phos                     3-[(dimethoxyphos-                                                                       
                          1-phenylethyl ester                                                                      

Chemical Structure

crufomate    montrel      phosphoramidic        C12 H19 ClNO3 P          291.74     299-86-5                          
             ruelene      acid, methyl-,                                                                           
                          phenyl methyl ester                                                                      

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
demeton-     metasystox   phosporothioic        C6 H15 O3 PS2             230.3      919-86-8                          
  S -methyl    methyl       acid,  S -[2-(ethyl-                                                                      
             isosystox    thio)ethyl]  O,O -                                                                        
                          dimethyl ester                                                                           

Chemical Structure
diazinon     basudin      phosphorothioc        C12 H21 N2 O3 PS          304.38     333-41-5                          
             dazzel       acid,  O,O -diethyl                                                                       
             diazajet      O -[6-methyl-2-(1-                                                                       
             diazide      methylethyl)-4-                                                                          
             diazol       pyrimidinyl] ester                                                                       

Chemical Structure
dichlo-      ECP          phosphorothioic       C10 H13 Cl2 O3 PS         315.16     97-17-6                           
 fenthion    hexa-nema    acid,  O -(2,4-di-                                                                        
             mobilawn     chlorophenyl)  O,O -                                                                      
             nemacide     diethyl ester                                                                            

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
dichlorves   atgard       phosphoric acid,      C4 H7 Cl2 O4 P            220.98     62-73-7                           
             canogard     2,2-dichloro-                                                                            
             cekusan      ethenyl dimethyl                                                                         
             DDVP         ester                                                                                    

Chemical Structure

dicroto-     bidrin       phosphoric acid,      C8 H16 NO5 P             237.22     141-66-2                          
 phos        carbicron    3-(dimethylamino)-                                                                       
             ektafos      1-methyl-3-oxo-1-                                                                        
                          propenyl dimethyl                                                                        

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
dimethoate   cygon        phosphorodithioic     C5 H12 NO3 PS2            229.27     60-51-5                           
             daphene      acid,  O,O -dimethyl                                                                      
             dimeton       S -[2-(methylamine)-                                                                     
             ferkethion   2-exoethyl] ester                                                                        

Chemical Structure

dioxathion   delnav       phosphorodithioic     C12 H26 O6 P2 S4           456.56     78-34-2                           
             kavadel      acid,  S-S' -1,4-                                                                         
             navadel      diexane-2,3-diyl                                                                         
             ruphos        O,O,O',O' -tetra-                                                                        
                          ethyl ester                                                                              

Chemical Structure
disulfoton   dimaz        phosphorodithioic     C8 H19 O2 PS3             274.42     298-04-4                          
             disyston     acid,  O,O -diethyl                                                                       
             disystox      S -[2-(ethylthio)                                                                        
             frumin       ethyl] ester                                                                             

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
EPN                       phosphonothioic       C14 H14 NO4 PS           323.32     2104-64-5                         
                          acid, phenyl- O -                                                                         
                          ethyl  O -(4-nitro-                                                                       
                          phenyl) ester                                                                            

Chemical Structure

ethion       bladan       phosphorodithioic     C9 H22 O4 P2 S4            384.49     22756-17-8                        
             fosfono 50   acid,  S,S' -methy-                                                                       
             nialate      lene  O,O,O',O'-                                                                          
             redocid      tetramethyl ester                                                                        

Chemical Structure
fenamiphos   nemacur      phosphoramidic        C13 H22 NO3 PS           272.34     22224-92-6                        
                          acid, (1-methyl-                                                                         
                          ethyl)-ethyl 3-                                                                          
                          thio)phenyl ester                                                                        

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
fenchlor-    ectoral      phosphorothioic       C8 H8 Cl3 O3 PS           321.54     299-84-3                          
 phos        etrolene     acid,  O,O -dimethyl                                                                      
             korlane       O -(2,4,5-trichloro-                                                                     
             nanchlor     phenyl) ester                                                                            

Chemical Structure

fenitro-     accothion    phosphorothioic       C9 H12 NO5 PS            277.25     122-12-5                          
 thion       cyfen        acid,  O,O -dimethyl                                                                      
             cytel         O -(3-methyl-4-                                                                          
             felithion    nitrophenyl) pester                                                                      

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
fensulfo-    dasanit      phosphorothioic       C11 H17 O4 PS2            308.37     4824-78-6                         
 thion       terracur-P   acid,  O,O -diethyl                                                                       
                           O -[4-(methyl-                                                                           

Chemical Structure

fenthion     baycid       phosphorothioic       C10 H15 O3 PS2            278.34     55-38-9                           
             baytex       acid,  O,O -dimethyl                                                                      
             entex         O -[3-methyl-4-                                                                          
             lebaycid     (methylthio)phenyl]                                                                      
             mercaptophos ester                                                                                    

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
fonofos      Dyfonate      O -ethyl  S -phenyl    C10 H15 OPS2             246.3      944-22-9                          

Chemical Structure
formothion   aflix        phosphorodithioic     C6 H12 NO4 PS2            257.28     2540-32-1                         
             anthio       acid,  S -[2-(formyl-                                                                     
                          ethyl]  O,O -dimethyl                                                                     

Chemical Structure
fosthietan                phosphoramidic        C6 H12 NO3 PS2            241.       21548-32-3                        
                          acid, 1,3-                                                                               
                          ylidene-, diethyl                                                                        

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
hepteno-     hostaquick   phosphoric acid,      C9 H12 ClO4 P            250.63     23560-59-0                        
 phos        ragadan      7-chlorobicyclo-                                                                         
                          dien-6-yl dimethyl                                                                       

Chemical Structure
idofenphos   alfacron     phosphorothioic       C8 H8 Cl2 IO3 PS          412.99     18181-70-9                        
             nuvanol-N    acid,  O -(2,5-                                                                           
                          iodophenyl)  O,O -                                                                        
                          dimethyl ester                                                                           

Chemical Structure

isofenphos   oftanol      benzoic acid, 2-      C15 H24 NO4 PS           345.43     25311-71-1                        
                          oxy]-, 1-methyl-                                                                         
                          ethyl ester                                                                              

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
leptophos    Phosvel       O -(4-bromo-2,5-di-   C13 H10 BrCl2 O2 PS       412.1      21609-90-5                        
             Abar         chlorophenyl)  O -                                                                        
                          methyl phenylphos-                                                                       

Chemical Structure
malathion    carbetox     butanedioic acid,     C10 H19 O6 PS2            330.38     121-75-5                          
             carbefos     [(dimethoxyphos-                                                                         
             chemation    phinothioyl)thio]-,                                                                      
             cythion      diethyl ester                                                                            

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
mecarbam     afos         carbamic acid,        C10 H20 NO5 PS2           329.4      2595-54-2                         
             muratox      [[[(diethoxyphos-                                                                        
             pestan       phinothioyl)thio]-                                                                       
                          ethyl ester                                                                              

Chemical Structure
menazon      azidithion   phosphorodithioic     C6 H12 N5 O2 PS2           281.32     78-57-9                           
             saphizon     acid,  S -[(4,6-di-                                                                       
             saphos       amino-1,3,5-                                                                             
             sayfor       triazin-2-yl)-                                                                           
             syphos       methyl]  O,O -                                                                            
                          dimethyl ester                                                                           

Chemical Structure

mephosfolan  Cytrolane    diethyl(4-methyl-1,   C8 H16 NO3 PS2            269.3      950-10-7                          

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
methamido-   hamidop      phosphoramidothioic   C2 H8 NO2 PS             141.14     10265-92-6                        
 phos        monitor      acid,  O,S -dimethyl                                                                      
             tamaron      ester                                                                                    

Chemical Structure
methida-     supracide    phosphorodithioic     C6 H11 N2 O4 PS2           302.34     950-37-8                          
 thion       ultracide    acid,  S -[(5-                                                                            
                          4-thiadiazol-3(2 H)-                                                                      
                          yl)-methyl]  O,O -                                                                        
                          dimethyl ester                                                                           

Chemical Structure
mevinphos    gestid       2-butenoic acid,      C7 H13 O6 P              224.17     7786-34-7                         
             menite       3-[(dimethoxyphos-                                                                       
             phosdrin     phinyl)oxy]-,                                                                            
             phosfene     methyl ester                                                                             

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
monocro-     azodrin      phosphoric acid,      C7 H14 NO5 P             223.19     2157-98-4                         
 tophos      monocron     dimethyl 1-methyl-                                                                       
             nuvacron     3-(methylamino)-3-                                                                       

Chemical Structure
morpho-      ekatin       phosphorodithioic     C8 H16 NO4 PS2            285.34     144-41-2                          
 thion       morphotox    acid,  O,O -dimethyl                                                                      
                           S -[2-(4-morpho-                                                                         

Chemical Structure
naled        arthodibrom  phosphoric acid,      C4 H7 Br2 Cl2 O4 P         380.8      300-76-5                          
             bromex       1,2-dibromo-2,2-                                                                         
             dibrom       dichloroethyl                                                                            
                          dimethyl ester                                                                           

Chemical Structure

Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
omethoate    dimethoxon   phosphorothioic       C5 H10 NO4 PS            213.21     1113-02-6                         
             folimat      acid,  O,O -dimethyl                                                                      
                           S -[2-(methylamino)-                                                                     
                          2-oxoethyl] ester                                                                        

Chemical Structure
oxydeme-                  phosphorothioic       C6 H15 O4 PS2             246.3      301-12-2                          
 ton-                     acid,  S -[2-(ethyl-                                                                      
 methyl                   sulfinyl)ethyl]                                                                          
                           O,O -dimethyl ester                                                                      

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
parathion    alkron       phosphorothioic       C10 H14 NO5 PS           291.28     56-38-2                           
             alleron      acid,  O,O -diethyl                                                                       
             cerothion     O -(4-nitrophenyl)                                                                       
             danthion     ester                                                                                    

Chemical Structure

parathion-   amofos       phosphorothioic       C8 H10 NO5 PS            263.22     298-00-0                          
 methyl      dalf         acid,  O,O -dimethyl                                                                      
             metafos       O -(4-nitrophenyl)                                                                       
             metaphor     ester                                                                                    

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
phenthoate   pap          benzeneacetic acid,   C12 H17 O4 PS2            320.38     2597-03-2                         
             papthion     alpha-[(dimethoxy-                                                                       
             tanone       phosphinothioyl)-                                                                        
             cidial       thio]-, ethyl ester                                                                      

Chemical Structure

phorate      granutox     phosphorodithioic     C7 H17 O2P S3             260.39     298-02-2                          
             rampart      acid,  O,O -diethyl                                                                       
             thimet        S -[(ethylthio)methyl]                                                                   
             vegfru       ester                                                                                    

Chemical Structure
phosalone    azofene      phosphordithioic      C12 H15 ClNO4 PS2        367.82     2310-17-0                         
             benzphos     acid,  S -[(6-chloro-                                                                     
             rubitox      2-oxo-3(2 H)- benzoxa-                                                                     
             zolone       zolyl)methyl]  O,O -                                                                      
                          diethyl ester                                                                            

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
phosmet      decemthion   phosphorodithioic     C11 H12 NO2 PS2           317.33     732-11-6                          
             appa         acid,  S -[(1,3-di-                                                                       
             ftalophos    hydro-1,3-dioxo-2H-                                                                      
             imidan       isoindol-2-yl)methyl]                                                                    
             prolate       O,O -diethyl ester                                                                       

Chemical Structure
phospha-     dimeron      phosphoric acid,      C10 H19 ClNO5 P          299.72     13171-21-6                        
 midon       famfos       2-chloro-3-(diethyl-                                                                     
                          oxo-1-propenyl di-                                                                       
                          ethyl ester                                                                              

Chemical Structure
phosfolan    Cyolane      P,P-diethyl cyclic-   C7 H14 NO3 PS2            255.3      947-02-4                          
             Cyolan       ethylene ester of                                                                        
             Cyalane      phosphonodithiomido-                                                                     
             Cylan        carbonic acid                                                                            

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
phoxim       baythion     3,5-dioxa-6-aza-      C12 H15 N2 O3 PS          298.32     14816-18-3                        
             valexon      4-phosphaocta-6-ene-                                                                     
             volaton       S -nitrile, 4-ethoxy-                                                                    
                          7-phenyl, 4-sulfide                                                                      

Chemical Structure

profenofos   Curacron      O -(4-bromo-2-chloro- C11 H15 BrCl03 PS        373.6      41198-08-7                        
             Selecron     phenyl)  O -ethyl  S -                                                                     
                          propyl phosphoro-                                                                        

Chemical Structure
prothiofos   Tokuthion    dichlorophenyl  O -    C11 H15 Cl2 O2 PS2         345.2      34643-46-4                        
                          ethyl  S- propyl phos-

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
prothoate    fal          phosphorodithioic     C9 H20 NO3 PS2            285.39     2275-18-5                         
             fostion      acid,  O,O -diethyl                                                                       
             oleofac       S -[2-[1-methylethyl)-                                                                   
             telefos      amino]-2-oxo-ethyl]                                                                      

Chemical Structure
pyrimiphos-  fernex       phosphorothioic       C13 H24 N3 O3 PS          302.46     23505-41-1                        
 ethyl       primieid     acid,  O -[2-(diethyl-                                                                    
             primotec     amino)-6-methyl-4-                                                                       
                          pyrimidinyl]  O,O -                                                                       
                          diethyl ester                                                                            

Chemical Structure
pyrimiphos-  actellic     phosphorothioic       C11 H20 N3 O3 PS          274.4      29232-93-7                        
 methyl      actellifog   acid,  O -[2-(diethyl-                                                                    
             blex         amino)-6-methyl-4-                                                                       
             silosan      pyrimidinyl]  O,O -                                                                       
                          dimethyl ester                                                                           

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
pyrazophos   afugan       pyrazolo[1,5a]pyri-   C14 H20 N3 O5 PS          373.4      13457-18-6                        
             curamil      midine-6-carboxylic                                                                      
                          acid, 2-[(diethoxyd-                                                                     
                          5-methyl-, ethyl                                                                         

Chemical Structure
sulfotep     bladafume    thiodiphosphoric      C8 H20 O5 P2 S2            322.34     3689-24-5                         
             dithiofos    acid, tetraetyl                                                                          
             dithione     ester                                                                                    

Chemical Structure

sulprofos    Bolstar       O -ethyl  O -[4-       C12 H19 O2 PS3            322.4      35400-43-2                        
                          (methylthio) phenyl]
                          phenyl]  S -propyl                                                                        

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
temephos     abate        phosphorothioic       C16 H20 O6 P2 S3           466.48     3383-96-8                         
             abathion     acid,  O,O' -(thio-                                                                       
             biothion     di-4,1-phenylene)                                                                        
             difethos      O,O,O',O' -tetra-                                                                        
             nimitox      methyl ester                                                                             

Chemical Structure
TEPP         bladan       diphosphoric acid,    C8 H20 O7 P2              290.22     107-49-3                          
             bladex       tetraethyl ester                                                                         

Chemical Structure
tetrachlor-  appex        phosphoric acid,      C10 H9 Cl4 O4 P           365.96     961-11-5                          
 vinphos     gardcide     2-chloro-1-(2,4,5-                                                                       
             gardona      trichlorophenyl)-                                                                        
             rabon        ethenyl dimethyl                                                                         
             stirofos     ester                                                                                    

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
thiometon    ekatin       phosphorodithioic     C6 H15 O2 PS3             246.36     640-15-3                          
             intrathion   acid, S -[2-(ethyl-                                                                       
                          thio)ethyl]  O,O -                                                                        
                          dimethyl ester                                                                           

Chemical Structure
thionazin    cynem        phosphorothioic       C6 H13 N2 O3 PS           248.26     297-97-2                          
             nemafos      acid,  O,O -diethyl                                                                       
             zinophos      O -pyrazin-2-yl ester                                                                    

Chemical Structure

triamiphos   wepsin       phosphonic diamide,   C12 H19 N6 CP            294.34     1031-47-6                         
                           P -(5-amino-3-phenyl-                                                                    
                          1 H- 1,2,4-triazol-1-                                                                      
                          yl)- N,N,N' -tetra-                                                                       

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
triazophos   Hostathion    O,O -diethyl  O -(1H-  C12 H16 N3 O3 PS          313.3      24017-47-8                        
             HOE 2960     1.2.4-triazol-3-yl)                                                                      

Chemical Structure

trichlor-    anthion      phosphonic acid,      C4 H8 Cl3 O4 P            257.44     52-68-6                           
 fon         bovinox      (2,2,2-trichloro-                                                                        
             briton       1-hydroxyethyl)-,                                                                        
             cehuion      dimethyl ester                                                                           

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
trichlor-    agrisil      phosphonothioic       C10 H12 Cl3 O2 PS         333.6      327-98-0                          
 nat         agritox      acid, ethyl-,  O -                                                                        
                          ethyl  O -(2,4,5-                                                                         

Chemical Structure

trifenofos   RH 218        O -ethyl- S -propyl- O- C11 H14 Cl3 O3 PS         363.6      38524-82-2                        
                          phenyl) phosphoro                                                                        

Chemical Structure
Annex I.  (contd.)                                                                                            
Common name  Trade or     CAS chemical name     Molecular             Relative   CAS                               
             other name                         formula               molecular  Registry                          
                                                                      mass       number                            
vamidothion  kilyal       phosphorothioic       C8 H18 NO4 PS2            287.36     2275-23-2                         
             trucidor     acid,  O,O -dimethyl                                                                      
             vamidoate     S -[2-[[1-methyl-2-                                                                      

Chemical Structure

Annex II.  Organophosphorus pesticides: JMPR reviews, ADIs, Evaluation by IARC, Classification by
Hazard, FAO/WHO Data Sheets, IRPTC Data Profile and Legal Filea 
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Acephate      1984     0-0.0005       1985a
              1982     0-0.003        1983b                             +      III
              1981i     0-0.02         1982b
              1979i     0-0.02         1980b
              1978     0-0.02         1979a
              1976     0-0.02         1977b

Azinphos      1983i     no ADI         1984a                    +        +
-ethyl        1973     no ADI         1974b                                    IB

Azinphos      1974i                    1975b                    +        +      IB
-methyl                               1975a
              1973     0-0.0025       1974b
              1972i     0-0.0025       1973b
              1968     0-0.0025       1969b
              1965                    1965b
                       0-0.0025       1965a
              1963     0-0.0025       1964

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Bromophos     1984i     0-0.04         1985b
              1982i     0-0.04         1983b                    +        +      III
              1978i     0-0.04         1979a
              1977     0-0.04         1978b
              1975i     0-0.006        1976b
                       (temporary)    1976a
              1972     0-0.006        1973b
                       (temporary)    1973a

Bromophos     1978i     0-0.003        1979a                    +        +      IB
-ethyl        1977i     0-0.003        1978b
              1975     0-0.003        1976b
              1972     0-0.003        1973b
                       (temporary)    1973a

Carbophen-    1983i     0-0.0005       1984a                    +        +      IB
othion        1980     0-0.0005       1981b
              1979     0-0.0005       1980b
              1977     0-0.0002       1978b
                       (temporary)    1978a
              1976     temporary      1977b
                       ADI withdrawn
              1972     0-0.005        1973b

Chlorfen-     1971     0-0.002        1972b                    +        +      IA
vinphos                               1972a

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Chlorpy-      1983i     0-0.01         1984a                    +        +      II            No. 18       
rifos         1982     0-0.01         1983b                                                  (1975)
              1981i     0-0.001        1982b                                    
              1977     0-0.001        1978b
              1975i     0-0.0015       1976b
              1974i     0-0.0015       1975b
              1972     0-0.0015       1973b

Chlorpy-      1979i     0-0.01         1980b                    +        +                    No. 33       
rifos-                                1980a                                                  (1978)
methyl        1975     0-0.01         1976b                                    II

Chlorthion    1965     no ADI         1965b
                                      1965a                                    -
              1963     no ADI         1964

Coumaphos     1983i     ADI withdrawn  1984a                    +        +      IA
              1980i     ADI Withdrawn  1981b
              1978i     0-0.005        1979b
              1975i     0-0.005        1976b
              1972i     0-0.0005       1973b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
              1968     0-0.0005       1969b

Crufomate     1972i     0-0.1          1973b                                    III
              1968     0-0.1          1969b

Cyano-        1983     ADI withdrawn  1984a                                    II
fenphos       1982i     0-0.001        1983b
              1980     0-0.001        1981b
              1978i     0-0.005        1979a

Cyano-        1975     0-0.005        1976b
fenphos                (temporary)

Demeton       1983i     no ADI         1984a                    +        +
(see also     1982     ADI withdrawn  1983a
disulfoton)   1975     0-0.005        1976b                                    IA            No. 60 
                                                                                             (in prep)
              1967i     0-0.0025       1968b
              1965     0-0.0025       1965b
              1963     0-0.0025       1964

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Demeton- S -   1984     no ADI         1985b
methyl and    1983i     no ADI         1984a                    +        +      IB
Related       1982     ADI withdrawn  1983a
Compounds     1979i     0-0.005 (the   1980b                           
(see also              total demeton-
oxydemeton-             S -methyl,     1980a                                    IB
methyl for             demeton- S -
1963 to 1968           methyl sulfo-
evaluations)           xide and deme-
                       ton- S -methyl
                       sulfone not
                       to exceed
                       this figure)
              1973     0-0.005 (the   1974b
                       total demeton  1974a
                       - S -methyl,
                       demeton- S -
                       methyl sulf-
                       oxide and
                       demeton- S -
                       methyl sulfone
                       not to exceed
                       this figure)

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Demeton-      1984     no ADI         1985b
 S -methyl     1983i     no ADI         1984a      
sulfoxide     1982     ADI            1983a                                    IB
(see                   withdrawn
methyl for
1963 to 1968
(see demeton-
 S -methyl and
after 1968)

Dialifos      1982     ADI            1983a                                    II
              1978i     0-0.003        1979a
              1976     0-0.003        1977b

Diazinon      1979i     0-0.002        1983a                    +        +      II            No. 45/1979
              1975i     0-0.002        1976b
              1970     0-0.002        1971b
              1968i     0-0.002        1969b
              1967i     0-0.002        1968b
              1966     0-0.002        1969b
              1965     0-0.002        1965b
              1963     no ADI         1964                              +

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Dichlorvos    1977     0-0.004        1978b        Vol 20      +        +      IB            No. 2 (1978)
                                                   p.97                                      (Rev. 1)
              1974i     0-0.004        1975b
              1970     0-0.004        1971b
              1969i     0-0.004        1970b
              1967                    1968b
                       0-0.004        1968a
              1966                    1967b
                       0-0.004        1967a
              1965     no ADI         1965b

Dimethoate    1984     0-0.002        1985b
              1983i     0-0.02         1984a                    +        +                    No. 42       
              1978i     0-0.02         1979a                                                  (1980)
              1977i     0-0.02         1978b        Vol. 15                     II
                                                   page 177
              1970i     0-0.02         1971b
              1967     0-0.02         1968b
              1966i     0-0.004        1967b
              1965     0-0.004        1965b
              1963     0-0.004        1964

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Disulfoton    1984i     0-0.002        1985b
(see also     1981i     0-0.002        1982b                    +        +                    No. 60 (in
demeton)                                                                                     prep.)
              1979i     0-0.002        1980b                                    IA
              1978i     0-0.002        1979a
              1975     0-0.002        1976b
              1973     0-0.001        1974b

Edifenphos    1981     0-0.003        1982b                             +      IB
              1979     0-0.003        1980b
              1976     0-0.003        1977b

Ethion        1985     0-0.0005       1986b
              1983i     0-0.001        1984a                    +        +      II
              1982     0-0.001        1983b
              1975i     0-0.005        1976b
              1972     0-0.005        1973b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
              1970i     0-0.00125      1971b
              1969i     0-0.00125      1970b
              1968     0-0.00125      1969b

Ethoprophos   1983     no ADI         1984a                                    IA            No. 70 (in

Etrimfos      1982     0-0.003        1983b                    +        +      II
              1980     0-0.003        1981b

Fenamiphos    1985     0-0.0003       1986b
              1980i     0-0.0006       1981b                                    IA
              1978i     0-0.0006       1979b
              1977i     0-0.0006       1978b
              1974     0-0.0006       1975b

Fenclorphos   1983i     0-0.01         1984a                    +        +      II
              1972i     0-0.01         1973b
              1968     0-0.01         1969b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Fenitro-      1984     0-0.003        1985a
thion         1983i     0-0.001        1974a                    +        +                    No. 30 
                       (temporary)                                                           (1977)
              1982     0-0.001        1983b
                                      1983a                                    II
              1979i     0-0.005        1980b
              1977     0-0.005        1978b
              1976i     0-0.005        1977b
              1974     0-0.005        1975b
              1969     0-0.001        1970b

Fensulf-      1983i     0-0.0003       1984a                    +        +        
othion        1982     0-0.0003       1983b
                                      1983a                                    IA            No. 44 
              1972     0-0.0003       1973b                                                  (1980)

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Fenthion      1983i     0-0.001        1984a                             +                    No. 23 
              1980     0-0.001        1981b                                                  (1976)
                                      1981a                                    IB
              1979     0-0.0005       1980b                                                 
              1978     0-0.0005       1979b
              1977i     0-0.0005       1978b
              1975     0-0.0005       1976b
              1971     0-0.0005       1972b

Formothion    1978i     0-0.02         1979a                    +        +      II
              1973     0-0.02         1974b
              1972i     no ADI         1973b
              1969     no ADI         1970b

Isophenphos   1984i     0-0.0005       1985a
              1982     0-0.0005       1983b                                    IB
              1981     0-0.0005       1982b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Iodophenphos                                                                   O             No. 43 
Leptophos     1978i     ADI            1979b                    +        +                    No. 38 
                       withdrawn      1979a                                                  (1979)
              1976i     0-0.001        1977a                                    IA
              1975     0-0.001        1976b
              1974     No ADI         1975b

Malathion     1984     0-0.02         1985b
              1977i     0-0.02         1978b        Vol. 30     +        +                    No. 29 
                                                   page 103                                  (1977)
              1975i     0-0.02         1976b                                    III
              1973i     0-0.02         1974b
              1970i     0-0.02         1971b
              1969i     0-0.02         1970b
              1968i     0-0.02         1969b
              1967i     0-0.02         1968b
              1966     0-0.02         1967b
              1965     0-0.02         1965b
              1963     0-0.02         1964

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Mecarbam      1985     0-0.0005       1986b
              1983     0-0.001        1984a                                    IB
              1980     0-0.001        1981b

Methacrifos   1982     0-0.0003       1983b                                    -
              1980     0-0.0003       1981b

Methamido-    1985     0-0.0006       1986b
phos          1984i     0-0.0004       1985a
              1982     0-0.0004       1983b                    +        +      IB
              1981i     0-0.002        1982b
              1979i     0-0.002        1980b
              1976     0-0.002        1977b

Methida-      1979i     0-0.005        1980b                    +        +      IB
thion                                 1980a
              1977i     0-0.005        1978a
              1975     0-0.005        1976b
              1972     0-0.005        1973b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe> :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Methyl parathion
(see parathionmethyl)

Mevinphos     1972     0-0.0015       1973b                    +        +      IA            No. 14 
                                      1973a                                                  (1975)
              1965     no ADI         1965b                             +
              1963     no ADI         1964

Monocroto-    1975     0-0.0006       1976b                    +        +      IB
phos                                  1976a
              1972     0-0.0003       1973b

Omethoate     1985     0-0.0003       1986b
              1984i     0-0.0005       1985a
              1981     0-0.0005       1982b                                    IB
              1980i     0-0.0005       1981b
              1979     0-0.0005       1980b
              1978     0-0.0005       1979b
              1975     0-0.0005       1976b
              1971     0-0.0005       1972b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Oxydemeton-   1968i     ADI            1969b
methyl                 withdrawn      1969a                                    IB
(referred in  1967     0-0.0025       1968b
1963 and 1965                         1968a
reports as    1965     0-0.0025       1965b
demeton- S -                           1965a
methyl        1963     0-0.0025       1964
demeton- S -
methyl and
related comp-
ounds for
after 1968)

Parathion     1984i     0-0.005        1985a
              1970i     0-0.005        1971b        Vol. 30     +        +      IA            No. 6 (1978)
                                                   page 153                                  (Rev. 1)
              1969i     0-0.005        1970b
              1967     0-0.005        1968b
              1965     0-0.005        1965b
              1963     0-0.005        1964

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                             by hazardg 
Parathion-    1984     0-0.02         1985b
(evaluated    1982     0-0.001        1983b        vol. page   +        +        IA          No. 7 (1978)
under methyl           (temporary)                 30-131                                    (Rev. 1)
parathion                             1983a
in 1963 and   1980     0-0.001        1981b
1965)                  (temporary)
              1979     0-0.001        1980b
              1978i     0-0.001        1979b
              1975     0-0.001        1976b
              1972i     0-0.001        1973b
              1968     0-0.001        1969b
              1965     0-0.01         1965b
              1963     0-0.01         1964

Phenthoate    1984     0-0.003        1985b
              1981i     0-0.001        1982b                    +        +      II            No. 48 
                       (temporary)                                                           (1983)
              1980     0-0.001        1981b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Phorate       1985     0-0.0002       1986b
              1984i     0-0.0002       1985a
              1983     0-0.0002       1984a                    +        +      IA            No. 75 (in
                       (temporary)                                                           preparation)
              1982     0-0.0002       1983b
              1977     No ADI         1978b

Phosalone     1976i     0-0.006        1977b                    +        +      II
              1975i     0-0.006        1976b
              1972     0-0.006        1973b

Phosmet       1984i     0-0.02         1985b
              1981i     0-0.02         1982b                    +        +      II
              1979     0-0.02         1980b
              1978     0-0.005        1979b
              1977     -corrigenda    1978b
                       to 1976
                       evaluations -
              1977i     no ADI         1978a
              1976i     no ADI         1977b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Phosphamidon  1985     0-0.0005       1986b
              1982     0-0.001        1983b                    +        +      IA            No. 74 (in
                       (temporary)                                                           preparation)
              1974i     0-0.01         1975b
              1972i     0-0.001        1973b
              1969i     0-0.001        1970b                  
              1968     0-0.001        1969b
              1966     0-0.001        1967b
              1965     no ADI         1965b
              1963     no ADI         1964

Phoxim        1984     0-0.001        1985b
              1983i     0-0.0005       1984a                                                  No. 31 (1978)
              1982     0-0.0005       1983b
                                      1983a                                    II

Pirimiphos-   1983     0-0.01         1984a                                                  No. 49 (1983)
methyl        1979i     0-0.01         1980b
              1977i     0-0.01         1978b                                    III
              1976     0-0.01         1977b
              1974     0-0.005        1975b

Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Temephos                                                       +        +      0             No. 8 (1978)
                                                                                             (Rev. 1)

Thiometon     1979     0-0.003        1980b                    +        +      IB
              1976i     0-0.005        1977b
              1973     0-0.005        1974b
              1969     no ADI         1970b

Triazophos    1983i     0-0.0002       1984a                                    IB
              1982     0-0.0002       1983b


Annex II.  (contd.)
Compound      Year of  ADIb            Evaluation   IARCd        Availability    WHO recom-    FAO/WHO Data
              JMPR     (mg/kg body    by JMPRc :    Evaluation     of IRPTCe :   mended clas-  Sheets on
              meeting  weight)        Published    of Carcino- Data     Legal  sification    Pesticidesh 
                                      in: FAO/WHO  genicity    Profile  filef   of pesticides
                                                                               by hazardg 
Trichlorfon   1978     0-0.01         1979b                    +        +      III           No. 27 (1977)
              1975     0-0.005        1976b        Vol. 30
                       (temporary)                 page 207
              1971     0-0.01         1972b

Trichloronat  1971     no ADI         1972b                    +        +      IA

Vamidothion   1985     0-0.0003       1986b
              1982     0-0.0003       1983b                    +        +      IB
              1973     no ADI         1974b
a    Adapted from: Vettorazzi & van den Hurk (1984).
b    ADI = acceptable daily intake.
c    JMPR = Joint Meeting on Pesticide Residues (FAO/WHO).
d    IARC = International Agency for Research on Cancer (WHO, Lyons, France).
e    IRPTC = International Register of Potentially Toxic Chemicals (UNEP, Geneva).
f    From: IRPTC (1983).
g    From: WHO (1984a). See this reference for classification of organophosphates not mentioned in 
    this annex.  

     The hazard referred to in this Classification is the acute risk for health (that is, the risk of 
     single or multiple exposures over a relatively short period of time) that might be encountered
     accidentally by any person handling the product in accordance with the directions for handling 
     by the manufacturer or in accordance with the rules laid down for storage and transportation 
     by competent international bodies. 

Classification relates to the technical material, and not to the formulated 
Class                                        LD50 for the rat (mg/kg body weight)
                                    Oral                            Dermal
                           Solids         Liquids          Solids         Liquids
IA  Extremely hazardous    5 or less      20 or less       10 or less     40 or less
IB  Highly hazardous       5 - 50         20 - 200         10 - 100       40 - 400
II  Moderately hazardous   50 - 500       200 - 2000       100 - 1000     400 - 4000
III Slightly hazardous     over 500       over 2000        over 1000      Over 4000
O   Unlikely to present
    acute hazard in normal 
h     WHO/FAO Data Sheets on Pesticides with number and year of appearance.
i     No toxicological evaluation - residues only.

 N.B.  References to Annex II are listed in the reference list of the main document.

Annex III.  LD50s and no-observed-adverse-effect levels in animals
Chemical    Acute LD50                       No-observed-adverse-effect level in      Reference
            (mg/kg body weight)a              animals (rats unless otherwise stated)
            Oral              Dermal         (mg/kg     (mg/kg body    Duration 
                                             diet)      weight)        of test
Azinophos-  16.4                             2.5        0.125          2 years        FAO/WHO (1974b)
methyl      80 (guinea-pig)                  5 (dog)    0.125 (dog)    2 years

Bromophos-  71 - 127          1366 (rabbit)             0.78           2 years        FAO/WHO (1976b)
ethyl                                        10 (dog)   0.26 (dog)     2 years
            225 - 550 (mice)

Bromophos   3750 - 7700                      20 (dog)   0.5 (dog)      1 year         FAO/WHO (1978b)
            2829 - 5850                                 0.4 (man)      4 weeks
            720 (rabbit)

Carbopheno- 32.3              1270 (rabbit)  3          0.15           3 generations  FAO/WHO (1980b)
thion                                                   0.02 (dog)     3 months
                                                        0.01 (man)     1 month

Chlorfen-   10 - 39           31 - 108,      1          0.05           3 months       FAO/WHO (1972b)
vinphos     117 - 200 (mice)  417 - 4700     1 dog      0.05 (dog)     16 weeks
            300 - 1000
            > 12 000 (dog)

Chlorpyr-   135 - 163         approximately             0.1            2 years        FAO/WHO (1982b)
ifos                          2000
            500 (guinea-pig)  (rabbit)                  0.1 (dog)      90 days
            32 (chicken)                                0.1 (man)      1 month
            1000 - 2000

Crufomate   770 - 950                        40         2              2 year         FAO/WHO (1969b)
            400 - 600                        40 (dog)   1 dog          75 days

Demeton     2.5 - 12

Annex III.  (contd.)
Chemical    Acute LD50                       No-observed-adverse-effect level in      Reference
            (mg/kg body weight)a              animals (rats unless otherwise stated)
            Oral              Dermal         (mg/kg     (mg/kg body    Duration 
                                             diet)      weight)        of test
Demeton- S - 57 - 106          302
methyl      110 (guinea-pig)

Diazinon    300 - 850         > 2150         2          0.1            90 days        FAO/WHO (1971b)
                                                        0.02 (dog)     31 days
                                                        0.05 (monkey)  2 years
                                                        0.02 (man)     37 days

Dichlorvos  56 - 108          75 - 210                  0.033 (man)    28 days        FAO/WHO (1977b)

                                             5          0.25           15 weeks
Dimethoate  320 - 380                                   0.2 (man)      57 days        FAO/WHO (1985b)
            15 (pheasant)
            40 (duck)

Dioxathion  43                235            3          0.15           13 weeks       FAO/WHO (1969b)
                                                        0.075 (dog)    90 days
                                                        0.075 (man)    28 days

Disulfoton  2.6 - 8.6         ca 20          1          0.05            2 years       FAO/WHO (1976b)
                                             1 (dog)    0.025 (dog)    12 weeks
                                                        0.075 (man)    30 days

Ethion      24.4 - 208        915            3          0.15           13 weeks       FAO/WHO (1986b)
                              (rabbit)                  0.125 (dog)    90 days

Fenamiphos  15.3 - 19.4       500            3          0.17           2 years        FAO/WHO (1986b)
            10 (dog)                         1 (dog)    0.025 (dog)    2 years
            75 - 100
            12 (hen)

Fenchlor-   1740              2000                      0.5            2 years        FAO/WHO (1969b)
phos                                                    1 (dog)        2 years

Annex III.  (contd.)
Chemical    Acute LD50                       No-observed-adverse-effect level in      Reference
            (mg/kg body weight)a              animals (rats unless otherwise stated)
            Oral              Dermal         (mg/kg     (mg/kg body    Duration 
                                             diet)      weight)        of test
Fenitro-    250 - 500         > 3000         5          0.25           34 weeks       FAO/WHO (1985b)
thion       870 (mice)        (mice)         10 (dog)   0.3 (dog)      12 months

Fenthion    190 - 315         330 - 500      3          0.15           2 years        FAO/WH0 (1981b)
                                             3 (dog)    0.09           2 years
                                                        0.07 (monkey)  1 year
                                                        0.02 (man)       -

Formothion  365 - 500         > 1000         20         1              2 years        FAO/WHO (1974b)
                                             40 (dog)   1 (dog)        2 years

Malathion   2800              4100           100        5              2 years        FAO/WHO (1967b)
                              (rabbit)                  0.2 (man)      88 days

Methida-    25 - 54           1546 - 1663    4          0.2            104 weeks      FAO/WHO (1976b)
thion       25 - 20 (mice)                              0.25 (monkey)  23 months
                                                        0.11 (man)     6 weeks

Mevinphos   3 - 12            1 - 90         0.37       0.02           2 years        FAO/WHO (1973b)
            7 - 18 (mice)     16 - 34                   0.025 (dog)    2 years
                              (rabbit)                  0.014 (man)    30 days

Monocroto-  14 - 23           336            0.5        0.025          12 weeks       FAO/WHO (1973b)
phos                          (rabbit)       0.5 (dog)  0.0125 (dog)   13 weeks

Omethoate   ca 50             700            1          0.05           3 months       FAO/WHO (1986b)
                                                        0.025 (dog)    12 months

Parathion   3.6 - 13          6.8 - 21                  0.05 (man)     3 weeks        FAO/WHO (1967b)

Parathion-                                   2          0.1            2 years        FAO/WHO (1985b)
methyl      14 - 24           67                        0.3 (man)      30 days

Annex III.  (contd.)
Chemical    Acute LD50                       No-observed-adverse-effect level in      Reference
            (mg/kg body weight)a              animals (rats unless otherwise stated)
            Oral              Dermal         (mg/kg     (mg/kg body    Duration 
                                             diet)      weight)        of test
Phosalone   120 - 170         1500           25         1.25           2 years        FAO/WHO (1973b)
            180 (mice)        > 1000         25 (dog)   0.625          2 years
            380 (guinea-pig)
            290 (pheasant)

Phospha-    17 - 30           374 - 530      2          0.1            12 weeks       FAO/WHO (1986)
midon                                                   0.5 (dog)      90 days

Pirimiphos- 2050              > 2000         10         0.5            2 years        FAO/WHO (1977b)
methyl                        (rabbit)       5 (mouse)  0.5 (mouse)    80 weeks
            1180 (mice)                                 0.25 (man)     28 days
            1000 - 2000
            1150 - 2300
            30 - 60 (hen)

Thiometon   120 - 130         > 1000         2.5        0.12           2 years        FAO/WHO (1980b)
                                             6 (dog)    0.5 (dog)      2 years

Trichlorfon 560 - 630         > 2000         50         2.5            2 years        FAO/WHO (1979b)
                                             50 (dog)   1.25 (dog)     4 years (dog)
a   From: Worthing (1983).
    N.B.  This reference is listed in the reference list of the main document.

Annex IV.  Abbreviations used in the document

ACh          acetylcholine                                          
AChE         acetylcholinesterase                                   
ACTH         adrenocorticotropic hormone                            
ADI          acceptable daily intake                                
ChE          cholinesterase                                         
CNS          central nervous system                                 
DDE          dichlorodiphenyldichloroethylene                       
DDT          dichlorodiphenyltrichloroethane                        
DEF           S,S,S -tributyl phosphorotrithioate                    
DFP          di-isopropyl fluorophosphate                           
EEG          electroencephalogram                                   
EMG          electromyography                                       
EPN           o -ethyl- O -(4-nitrophenyl)phenylphosphonothioate      
FAO          Food and Agricultural Organization (United Nations)    
IARC         International Agency for Research on Cancer            
im           intramuscular                                          
IPCS         International Programme on Chemical Safety             
             (World Health Organization)                            
IRPTC        International Register of Potentially Toxic            
             Chemicals (United Nations Environment Programme)       
iv           intravenous                                            
JMPR         FAO/WHO Joint Meeting on Pesticide Residues            
MFO          mixed-function oxidase                                 
MLD          minimum lethal dose                                    
MRL          maximum residue limit                                  
NAD          nicotinamide-adenine-dinucleotide                      
NADPH        nicotinamide-adenine-dinucleotide phosphate            
             (reduced form)                                         

NTE          neuropathy target esterase (formerly                   
             neurotoxic esterase)                                   
OMPA         octamethylpyrophosphorictetramide                      
2-PAM        pyridine-2-aldoxime methyl chloride                    
pseudoChE    pseudocholinesterase                                   
sc           subcutaneous                                           
TCDD         2,3,7,8-tetrachlorodibenzo-1,4-dioxin                  
TEPP         tetraethyl pyrophosphate                               
TOCP         tri- o -cresyl phosphate                                
UVR          ultraviolet radiation                                  


    See Also:
       Toxicological Abbreviations