WHO Food Additives Series, 1972, No. 4
EVALUATION OF MERCURY, LEAD, CADMIUM
AND THE FOOD ADDITIVES AMARANTH,
DIETHYLPYROCARBONATE, AND OCTYL GALLATE
The evaluations contained in this publication were prepared by the
Joint FAO/WHO Expert Committee on Food Additives which met in Geneva,
4-12 April 19721
World Health Organization
Geneva
1972
1 Sixteenth Report of the Joint FAO/WHO Expert Committee on Food
Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 505; FAO
Nutrition Meetings Report Series, 1972, No. 51.
LEAD
Consideration of lead intake by man must take into account other
routes in addition to ingestion in food. Air contains concentrations
of lead that vary with the degree of urbanization and industrial
pollution. Therefore, in the course of respiration lead is inhaled
and some of it is then absorbed into the body. Similarly, drinking
water may contain concentrations of lead which differ according to
geographical location. Thus food, water and air contribute to the
total intake of lead, and their relative importance with respect to
the resulting body burden of lead depends on the proportion of lead
retained in the body from each source.
The same general considerations with respect to sources, levels and
methods of analysis considered for mercury apply also for lead.
Sources
(a) Environmental sources
Soil. Lead is ubiquitous in soil. Levels of 8-20 mg/kg found in
non-cultivated soils indicate that it has always been present in man's
environment, although not necessarily at such high levels. In
cultivated soils levels up to 360 mg/kg have been reported. Near
industrial sources lead may reach 10 000 mg/kg or more.
Proximity to roads with high traffic density may contribute
substantially to soil levels (for example, 403 mg/kg in the top 5 cm
layer of soil). In addition, high levels of lead may occur in dust
settling in urban areas, and may result in direct contamination of
food. Surface contamination in situ of plants growing near highways
does occur. Lead is absorbed by edible and nonedible vegetation, so
that grasses, for instance in highly contaminated areas, may attain
levels of 20-60 mg/kg (Chow, 1970). The chemical forms of lead and
the various factors limiting their availability for uptake by plants,
e.g. type of soil, pH, etc., are other important considerations. Lead
enters the food chain through plants or through accidental ingestion
of soil. However, not all plants take up lead to an equal extent so
that the soil content of lead may remain high in spite of cultivation.
Lead accumulates similarly in food of animal origin from absorption
and retention of plant lead by farm animals.
Air. In rural areas levels of lead in air of 0.1 µg/m3 or less are
found. However, depending upon the degree of pollution due to
urbanization, the amounts of lead in city air range from 1-3 µg/m3,
and will occasionally be much higher under peak traffic conditions
(Ludwig et al., 1965; Miettinen, 1972).
On the basis of the information available, and depending upon the
degree of urbanization of the area concerned, its topographical
situation, weather conditions, and habitat, it may be assumed that the
intake of lead by inhalation in cities could on occasion be 100
µg/day. Lead-containing dusts are present in many manufacturing
processes and may add to the lead content in all foods to a small
degree (Shy et al., 1971). Infants and children may be exposed to
proportionally higher levels than adults because the higher metabolic
rate would entail the inhalation of two to three times the amount of a
given air pollutant (Shibko, 1972).
Some unconfirmed reports have suggested that a very small proportion
of the total lead in urban air might be in organic form. This is a
separate problem that needs to be considered by experts in air
pollution. The contribution of lead from air to the total intake can
be estimated solely from the total body burden.
Also contributing to the atmospheric level of lead are industrial lead
smelters, disposal of discarded batteries and other lead-containing
materials, burning of garbage and old painted wood, weathering of old
lead-containing paints on buildings, as well as the burning of coal
and fuel oil.
A source of lead that calls for particular consideration is the lead
tetra-alkyls used as petrol (gasoline) additives. The lead derived
from petrol additives contributes not only to the intake through
inhalation but also to the intake through ingestion as a result of
fallout from vehicle exhausts on nearby food crops. An increased lead
content may be found in crops at distances up to 50 m from highways,
depending on weather conditions and traffic volume (Motto et al.,
1970). Although formerly significant, in many countries the
atmospheric contributions to total lead levels derived from fossil
fuels is now less important compared with that from lead-containing
petrol additives. The very low atmospheric levels of alkyl lead
compounds in city air do not contribute significantly to the lead
problem.
Tobacco smoking may also contribute to lead intake by man (FAO/WHO,
1967). While atmospheric lead is present in relatively small
concentrations, this source assumes considerable importance because a
greater proportion of load is likely to be absorbed after inhalation
than after ingestion.
Water. Sea-water contains lead (0.003-0.20 mg/litre). Natural
water probably contains no more than 0.005 mg/litre but in the
presence of nitrate, ammonium salts or dissolved carbon dioxide the
water becomes plumbosolvent. This occurs in soft, slightly acid water
in older properties where lead piping is still in use (Schroeder &
Balassa, 1961). Levels of lead as high as 25 mg/litre have been
reported (Egan, 1972). Hard waters normally lay down a protective
coat of calcium salts which avoids this hazard, but even this form of
protection may not apply if naturally hard water also has a high
organic and nitrate content.
The levels of lead encountered in water supplies are probably about
0.01 mg/litre. However, the International standards for drinking
water (WHO, 1971) suggest a tentative limit for lead of 0.1 g litre.
Assuming a consumption of 2.5 litres of water per day the maximum lead
intake from this source would be 250 µg; this would contribute
significantly to the total amount of lead taken in by man.
Another possible source of contamination that has aroused concern is
lead present in food containers, in the widest sense, including lead
water-piping. Depending on pH, mineralization and other factors,
traces of lead may leach into food or drink from such containers. It
is recognized that the use of lead plumbing for drinking-water
supplies and especially for soft or softened water is not advisable.
There is little information on the ability of fish and shellfish to
accumulate lead from contaminated waters. Wettenberg (1966) reported
concentrations of 1.4 ppm in muscle of fish from a lake near a lead
mine. High values have been reported by FDA in 1971 of lead in
shellfish (up to 10 ppm), in certain contaminated areas in the United
States.
(b) Industrial Sources
Lead is used in a large number of industrial processes. In people
exposed occupationally to lead fumes or dust the intake of lead by
inhalation and by ingestion will be increased. Therefore, part of the
body burden of lead in particular individuals may be contributed by
industrial exposure. As mentioned below, industrial emissions near
smelting works may frequently add lead dust contamination to other
environmental sources.
Lead-containing dusts are present throughout all manufacturing
processes and gradually add to the lead content of all foods to a
small degree (Miettinen, 1972; Shy et al., 1971). In the past, lead
impurities in food additives were another source of lead. Modern
legislation and trade practice, and the adoption, in food additive
specifications, of limits for lead recommended in previous reports of
the Committee, have virtually eliminated this hazard. Lead smelters
and dumps where lead-containing material such as old batteries has
been discarded or burnt may contribute to localized environmental
contamination of the food supply.
(c) Agricultural sources
The use of lead arsenate in agriculture has diminished. Where its use
is still permitted on orchard crops, it contributes only a small
proportion of the total intake of lead by man. The use of
lead-containing pesticides in tobacco has likewise diminished although
it might have contributed significantly to the lead intake by smokers.
More recent analytical data however are required.
(d) Other sources
Consideration of lead in food and water must take into account lead
contamination of the domestic environment. Old lead paint on walls
and woodwork, and paints on toys may be important sources of excessive
lead intake in children (Chisolm, 1971; Chisolm & Kaplan, 1968).
Lead glazes are used on ceramic kitchenware, earthenware and stoneware
vessels because they allow more flexibility in the kiln temperatures
for firing pottery. Lead may also occur in decorative glazes on some
pottery. The leaching of lead from inadequately fired glazes has been
investigated and it is known to present serious health hazards in
vessels used as containers for acidic foods and beverages. Lead
glazes for decorative purposes should not be placed in contact with
food. Pewter containers and tinned copperware, in which the use of
impure tin was a frequent source of lead, have now largely been
replaced by aluminium and stainless steel containers.
Tinplate cans with soldered seams have been investigated as possible
sources of lead contamination for a variety of foods. In a survey
carried out in the United Kingdom the mean lead concentration for
canned baby food was about 0.24 mg/kg compared with a level of 0.04
mg/kg for baby food in jars (U.K. Report, 1972). The tin coating
itself contains little lead, if any, but the solder used for the seam
may contain up to 98% lead.
Methods of analysis
In the basic method for the estimation of traces of lead in biological
material, the sample is ashed or wet oxidized under controlled
conditions. Lead is removed from the digest and concentrated by
extraction as dithiocarbamate complex. The amount of lead present is
estimated by atomic absorption spectrophotometry using the 283.3 nm
line, due regard being given to the recovery of lead in control
experiments. The method given by the International Union of Pure and
Applied Chemistry for traces of lead in food is currently under
revision to include atomic absorption spectrephotometry (IUPAC, 1965).
Biological data
Intake, retention and absorption
Lead is a non-essential element for man, with a toxic potention for
all biological systems. It accumulates in human tissues particularly
in the bones, liver and kidneys. There is an unavoidable total
daily intake from inhalation and ingestion of various forms of lead
in the human environment, which is considerably greater than the
total actually absorbed.
Food and water are the major sources of ingestion of lead. In
addition, some of the inhaled lead is cleared from the respiratory
tract and swallowed. Lead in food may be added to by a number of
possible sources of environmental contamination, mentioned previously.
When results of total diet studies for lead in industrialized
communities are examined, traces of lead are found to be generally
distributed over all food groups, including water; and the intake is
of the order of 200-300 µg per person per day. Certain foods such as
kidneys and liver tend to have higher than average levels (Cheftel,
1950). Total diet surveys in the United Kingdom suggest a mean daily
intake of 0.22 mg lead although individual results show considerable
and as yet unexplained variations. Canadian reports suggest a rather
lower intake of 0.15 mg lead per day while United States reports
indicate levels of 0.25-0.30 mg lead per day (Kehoe, 1964). Romanian
sources quote 0.7-1.0 mg lead per day (Fleming, 1964). An estimate of
lead ingested by children between one and three years of age was given
as 0.112-0.165 mg lead per day (King, 1971). Further reports suggest
that most food in North America reaches a level of less than 0.5 mg/kg
lead in individual items (Schroeder & Balassa, 1961; Kehoe et al.,
1940). Levels of lead in milk seem to have risen slightly over the
past 20-30 years (Lewis, 1966) but there is no evidence of any real
increase in dietary lead during recent decades (United Kingdom report,
1972). Recent comparisons of lead in food in North America with those
obtained over 20 years earlier also do not suggest any increase in
lead intake by man from this source.
The major routes of entry of lead into the body are the
gastrointestinal tract and the lungs. Under conditions of normal
dietary intake of lead, absorption from the gut is estimated to be
6-7% (Kehoe, 1961). The United Kingdom estimate is 5-10% (United
Kingdom report, 1972). Individuals given daily doses of 3 or 6 mg
lead absorbed 20-30% (Imamura, 1957). These different figures may
reflect the effects of higher loads and also nutritional differences,
since calcium, phosphorus and other substances, e.g. phytic acid, can
affect the absorption of dietary lead (Monier-Willims, 1949). There
is some experimental evidence in animals that suggests the possibility
that very young infants may absorb considerably more lead from the
diet than adults (Kostial et al., 1971).
As the lead concentration in ambient air has been shown to vary from
less than 0.1 µg/m3 to more than 30 µg/m3 in different localities,
estimates of the total lead inhaled must necessarily cover a wide
range. Figures for inhaled lead have been quoted for an urban
population to be between 0.01 and 0.10 mg per day. (United States
public Health Service, 1965), the amount being dependent on the total
ventilation of the subject as well as on the lead level in ambient
air. It is likely that once lead is deposited in the nonciliated
peripheral part of the lung it is completely absorbed, whilst lead
deposited on ciliary surfaces will be mostly translocated to the
gastrointestinal tract and handled subsequently in the same way as
ingested lead. A study utilizing a 212Pb labelled aerosol of mass
median diameter of 0.2 µm showed a deposition of 14-45% of the mount
inhaled, less than 8% of which was deposited in the tracheo bronchial
tree (Hursh et al., 1969). However, the pulmonary deposition of
inhaled particles is dependent on their physical characteristics as
well as on the respiratory pattern. Because of the variability of
these factors it is not possible to arrive at a precise estimate of
the degree of absorption of inhaled lead.
Estimates for absorption have mostly ranged from 25-50% of inhaled
lead (Kehoe, 1964). On this basis the estimated daily absorption from
the ambient air in Cincinnati was 0.01-0.02 mg (Goldsmith & Hexter,
1967). A study of some of the physical characteristics of particles
from vehicle exhausts suggests that the estimate of 25-50% absorption
of inhaled lead may be too high (Lawther at al., 1972).
Lead is transported mainly on the surface of the red blood cells, and
is distributed throughout the body, undergoing cumulative storage in
all tissues and organs. The largest amounts are stored in bone where
lead is first deposited as a colloidal compound, and later as
crystalline material. Much lower quantities of lead are found in the
liver and kidneys. The deposition and removal of lead from bone is
governed by the same factors that control the movement of calcium.
The total body burden of an adult is estimated to be 100-400 mg, but
it is not certain whether this burden of lead is close to the toxic
threshold.
Various ranges may be cited for whole blood levels of lead: 100-500
ng/ml (mean 300 ng/ml); 110-210 ng/ml or 250-400 ng/ml (Anon., 1966).
Kehoe (1961) gave upper limits of 400 and 800 ng/ml for children and
adults respectively, but these values far exceed what would be
regarded as the upper range of normal today. A WHO survey of 15
countries gave 150-330 ng/mi (WHO, 1965). Lead enters mother's milk;
it may not cross the placental barrier, nevertheless the foetus is
known to retain lead (Anon., 1966). Levels of lead in the blood of
newborn babies show a direct relationship to the levels present in the
maternal blood. (Hass, T. H. et al., 1972).
Most of the ingested lead is excreted in the faeces and these contain
usually 0.22-0.25 mg lead per day. Usually lead is excreted in
inorganic form in the urine of normal subjects but in exposed
individuals it is excreted in inorganic and lipid extractable form
(50% or more of total urinary lead) (Dinischiotu et al., 1960). The
average total urinary lead excretion amounts to 0.05 mg per day (0.03
mg/litre) but as much as 0.2 mg has been found in symptomless people
(Monier-Willlams, 1949). Very small amounts are excreted in the sweat
and hair. Radioactive lead balance studies have shown intakes of 0.41
mg per day from food and fluids and 0.01 mg from air against a hair
output of 0.088 mg. About 0.001 mg per day was retained (Howells,
1967). In mother estimate, intake from food was 0.26 mg lead per day,
water 0.02 mg against an output of 0.175 mg in faeces, 0.03 mg in
urine, 0.09 mg in sweat and hair, 0.007 mg having been stored in bone
(Schroeder & Tipton, 1968).
While under ordinary circumstances absorption of lead exceeds
excretion, at very low intakes, faecal excretion keeps pace with
absorption so that little accumulation occurs in tissues. A rise in
blood and urine lead levels is therefore evidence of increased
absorption without necessarily being associated with any detectable
biological change.
Lead toxicity
The lead absorbed from lungs and gastrointestinal tract eventually
distributes throughout all tissues and at least 95% of the total body
burden tends to accumulate in the bones. The amount of lead in bone
will depend upon the level of past exposure and is found to vary
between individuals, whereas soft-tissue concentrations remain
relatively constant. It is not possible to maintain a clear
distinction between lead absorption compatible with normal body
function and subclinical lead intoxication, when the evidence
available shows only that interference with some metabolic process of
unknown significance in the body has occurred. The pattern of lead
absorption, metabolism and body storage seems to be similar in all
animal species examined. The kidneys, the liver, the bone marrow and
the brain are the target organs of toxic effects.
At any given time the blood level of lead represents an expression of
a balance between absorption from environmental sources and excretion
in urine, faeces, sweat, hair, soft tissues, bone marrow and bone, but
bears no direct relationship to the threshold for overt poisoning.
The majority of occupationally unexposed people have blood lead levels
lying between 150-250 ng/ml for adults and children. Blood levels of
above 360 ng/ml in children and above 600-800 ng/ml in adults are
usually regarded as excessive and indicative of undue lead absorption
even if no symptoms are detected. Urinary lead levels of 150 µg/litre
are considered acceptable but higher levels indicate excessive
absorption. For other parameters the limits are haemoglobin 13 g for
men, urinary coproporphyrin 500 µg/iitre and urinary o-aminolevulonic
acid (ALA) 20 mg/litre (Gibson et al., 1968; British Medical Journal,
1968).
Lead significantly inhibits the enzymatic conversion of ALA to
prophobilinogen by ALA dehydrase and the final formation of heme by
the incorporation of iron into protoporphyrin IX. The inhibitory
actions result in increased urinary excretion of home precursors,
including porphobilinogen and coproporphyrin III. Erythrocyte
coproporphyrin and non-haemoglobin iron stores are increased.
Extracellular iron metabolism is not affected by lead, iron clearance
from adult plasma is normal, but in children it may be prolonged
(Waldron, 1966). Iron passes normally to bone marrow but utilization
for haemoglobin formation is decreased (Simpson et al., 1964). The
presence of basophilic stippling in erythrocytes is a feature of frank
lead poisoning and does not correlate with lead exposure; most
stippled cells are present in the bone marrow. The granules are
altered ribosomes (Waldron, 1966). Other cells have iron-positive
non-basophil granules and both granule types occur in some cells,
megaloblasts appear as well as arrests at metaphase of erythroblastic
nuclei (Beritic & Vandekar, 1956).
Mild lead poisoning is associated with slight reduction in nerve
conduction velocity. Peripheral nerve damage in lead exposed workers
was shown to be related to the degree of anaemia (Catton et al.,
1970). Lead palsy is probably due to direct action of lead on the
muscle as well as damage to nerve. Excessive ingestion of lead causes
inflammation of the gastrointestinal tract.
Renal damage which is rare in adults with plumbism but frequent in
children, results from direct cellular toxic action as shown by
intranuclear inclusion, aminoaciduria, glycosuria and other features
of the Falconi syndrome due to renal tubular damage have been
described in children with lead poisoning (Chisolm, 1962). In a
series of cases reported from Australia, 50% of cases of chronic
plumbism with lead nephropathy were also associated with gout and with
low urinary uric acid excretion (Emmerson, 1965; Morgan et al., 1966).
A correlation between childhood plumbism and the development of
nephropathy 10-40 years later has been noted in Australia. The
excessive initial absorption caused no symptoms. Bone lead of persons
dying from chronic nephritis was significantly higher than bone lead
of people dying from non-renal causes (Radosevic et al., 1961; Tepper,
1963). Heavy lead exposure with episodes of clinical plumbism
extending over 10 years caused nephropathy with renal failure in 15%
of 102 individuals affected, and hypertension developed later (Lilis
et al., 1968). In another study of 20-year exposure, 4% of the 53
cases had organic nephropathy.
In the course of a study carried out in mice given 25 ppm lead acetate
in drinking water, Schroeder et al., (1970) noted that the mean
lifespan of male animals was curtailed by 100 days compared with
controls maintained on leadfree diets. The lead concentration in
heart, lung, kidney, liver and spleen approached that found in human
tissues.
Poisoning
(a) Sources
Water standing in lead pipes overnight has given rise to lead
intoxication. Children have been poisoned by home-grown vegetables
from gardens whose soil had a high content of lead; cabbage, for
example, contained 5 mg/kg lead (Moncrieff et al., 1964); frying pans
with a tin coating with 29-58% of lead (British standard
specifications, 1964 = 25%) contaminated cooked food with 4-6 mg lead
per portion. Home-made wine and liquor has caused intoxication
through lead dissolved from pottery glaze (Klein et al., 1970) and car
radiators used in illegal distillation. "Devonshire colic" has been
caused by lead dissolved from base trays to give a concentration in
cider of 6 mg/litre (Walls, 1969). Gurkha soldiers fell ill following
ingestion of chilli powder adulterated with 10 800 ppm lead chromate
(Power et al., 1969). Many other accidental food contaminations have
been reported. Lead from solder used in canning processes is usually
not an important source of acute lead poisoning.
(b) Diagnosis
Of the diagnostic criteria, the most sensitive tests relate to the
interference with normal heme synthesis, as shown by the development
of anaemia, risein, urinary coproporphyrin level, urinary ALA
excretion and fall in red cell ALA dehydrase activity. Blood and
urine lead levels do not distinguish between toxicity and exposure.
Risein urinary ALA levels agree most closely with clinical evidence of
intoxication and may provide an earlier sign of lead absorption than
urinary coproporphyrin levels. Reduced ALA dehydrase activity is
probably the most sensitive indicator of exposure (Cramer & Selander,
1965; Bruin 9, Hoolboom, 1967). Basophil stippling is a poor
indicator of excess absorption. Hair concentrates lead and there is
some evidence that it may be a good indicator of excessive exposure.
Normal levels are about 24 mg/kg and in chronic poisoning may reach
280 mg/kg (Kopito et al., 1967). Urinary ALA levels and lead levels
in hair might provide suitable parameters in mass screening for
subclinical lead poisoning (Blanksma et al., 1969; Lin-Fu, 1970).
Lead intoxication is accompanied by effects on thyroid function at
various points of the pituitary-thyroid axis, but without change in
the level of protein bound iodine in the serum (Sandstead et al.,
1966).
An association has been shown between prolonged exposure to lead and
mortality from cerebrovascular accidents not associated with
hypertension (Hunt, 1970; Dingwall-Fordyce & Lane, 1963; Cramer &
Dahlberg, 1966). It has also been suggested that lead exposure may
aggravate liver cirrhosis (Butt, 1960).
The working group of the International Agency for Research on Cancer,
commenting on the evaluation of carcinogenic risk of chemicals to man
(IARC, 1972), concluded that there was no evidence to suggest that
exposure to lead compounds caused cancer of any site in man.
Dingwall-Fordyee & Lane (1963) in reporting the results of a follow-up
study of 425 persons who had previously been exposed to lead in an
accumulator factory, found no evidence to suggest that malignant
disease was associated with lead absorption. However, this is only
one epidemiological study of the possible relationship between
exposure to lead and the occurrence of human cancer. In animal
experiments a carcinogenic effect has been demonstrated but the levels
of lead acetate, which produced renal tumours in rats, exceed by far
the maximum tolerated dose for man (van Each et al., 1962).
Massive exposure to lead has caused reproductive and teratogenic
effects in animals. In man lead in high dosage has long been used as
an abortifacient but there is no evidence that it has any teratogenic
effects. A higher incidence of mitoses with secondary chromosomal
aberrations was seen in workers exposed to lead oxide compared with an
unexposed control group. In vitro studies with lead acetate
produced similar chromosomal abnormalities (Schwanitz et al., 1970).
A study of chromosomal changes in the lymphocytes of persons suffering
from chronic lead poisoning showed a modest percentage of aneuploidy
of the cells (Biscaldi et al., 1969). Earlier literature has
suggested mutagenic effects in chronic lead poisoning. Plumbism in
fathers seems to have an adverse effect on reproductive performance
and the survival of the offspring (Weller, 1915).
There is experimental evidence that the absorption of lead is high in
newborn rats and it has been suggested that this may also be the case
with very young human infants (Kostial et al., 1971). The suggestion
of a causal relationship between excessive lead absorption and mental
retardation in children was not borne out by investigation of blood
levels of lead in mentally-handicapped and normal control children
(Gordon et al., 1967).
(c) Clinical manifestations
Chronic lead poisoning is usually associated with anaemia, basophil
stippling of RBC, an elevated reticulocyte count, faulty maturation
and haemoglobinisation of RBC in bone marrow with, sometimes, an
additional haemolytic element. Adults usually have a normocytic and
normochromic or hypochromic anaemia which rarely falls below 9 g Hb.
Children may have a microcytic, hypochromic anaemia which may be more
severe (Waldron, 1966). A lead line may be seen in the gums in adults
but rarely in children. Renal tubular cell abnormalities may give
rise to a Falconi syndrome. There is some doubt whether chronic
exposure to low levels of lead can produce permanent renal damage.
Mild symptoms of tiredness, lassitude, abdominal discomfort, insomnia,
constipation or diarrhoea and nausea have been claimed to be
associated with continuous low dose exposure. The USSR includes also
broader subliminal effects associated with changes in conditioned
reflexes which may appear at levels of 250-300 ng/ml lead in blood
(Gusev, 1960).
Investigations on lead exposure
(a) Short-term studies
One experimental subject consumed 0.32 mg lead/day in his diet and in
addition, 3 mg/day lead chloride for 18 weeks. There was a
progressive increase in the output and concentration of lead in urine,
in the lead level in blood and in the amount of lead retained in the
body (Kehoe, 1965).
Three groups of men in (a) presymptomatic state, (b) with mild toxic
symptoms, (c) with severe poisoning, were examined for various
parameters. The urinary lead excretion was similar in all three
groups. Blood lead levels were poorly correlated with symptoms.
Haemoglobin, urinary coproporphyrin levels and urinary ALA levels
correlated well with clinical symptoms. Porphobilinogen in urine was
raised only in frank poisoning (Gibson et al., 1968).
(b) Long-term studies
Three experimental subjects consumed 0.32 mg lead/day in their diet
and in addition 2 mg lead chloride/day for two years, 1 mg lead
chloride/day for four years or 0.3 mg lead chloride/day for 60 weeks.
Those receiving 1 and 2 mg additional lead showed progressive rise in
urinary lead output and concentration and progressive rise in blood
lead level as well as in the quantity of lead retained in the body.
The urinary output and lead concentration increased slightly at 0.3 mg
lead/day and by 15 months it was calculated that 12 mg had accumulated
in the body. Blood lead levels were not raised. It was concluded
that a total dietary intake of 0.62 mg lead/day could not, within the
human lifetime, reach potentially dangerous blood levels and body
burden (Kehoe, 1965).
A group of 14 human volunteers underwent continuous exposure to
inhaled lead particulates for 23 hours a day over a period of five
months, under carefully controlled conditions providing a low
background of lead in food and water, and in the air inhaled which was
confirmed by a control group of six subjects. As a result of exposure
to a mean level of 10.9 µg lead/m3 of air, the level of blood lead
was virtually doubled while the o-aminolevulinic acid dehydrase (ALAD)
activity in red cells fell concomitantly. Measurements of urinary
porphobilinogen, ALA and coproporphyrin III revealed no increase from
pre-exposure levels. Follow-up of the subjects for several months
after the cessation of exposure revealed a return of ALAD and lead to
pre-exposure levels in blood. A further study along similar lines,
but with a mean atmospheric concentration of 3.5 µg lead/m3, revealed
only a very slight and delayed rise in blood lead and simultaneous
fall in ALAD. It is thus likely that 2-2.5 µg lead/m3 represents a
level below which no evidence of exposure is manifest, as judged by
the most sensitive indices considered to be applicable at the present
time (Golberg, 1972).
The human studies just described were preceded by continuous
inhalation exposure of rats and monkeys (M. mulatta) for one year to
levels of about 20 µg lead/m3. The resulting rise in blood lead
followed different patterns in the two species. The level of ALAD in
red cells fell in rats but was initially so low in monkeys that any
reduction in activity could not be measured. (ALAD is a vestigial
enzyme with no known function in the mature erythrocyte.)
Epidemiological evidence suggests that ALA dehydrase inhibition is
demonstrable at blood lead levels considered to be within normal
limits, i.e. 300-400 ng/ml (Members & Nikkanen, 1970). The
significance of these findings for man in terms of a health hazard is
at present unknown. It is believed that man can cope with the limited
effects of low or moderate lead exposure in the short term for there
is at present no evidence that such specific metabolic interference as
is demonstrated by a fall in red cell ALA dehydrase is associated with
any effects on the health of the individual. Uncertainty exists over
the long-term consequences of a persistent intake of lead at levels
not toxic in the short term, and the relation of such effects, if any,
alone or in combination with other factors, to the development of
chronic degenerative conditions (Shibko, 1972). The very low
atmospheric levels of alkyl lead compounds in city air do not
contribute significantly to the lead problem.
EVALUATION
It is evident that with present environmental exposures lead
accumulates in man with age but people differ in the effectiveness
with which they absorb and eliminate lead. The environmental
exposures to lead now existing in industrialized communities are
sufficient to cause tissue accumulation estimated to reach about 230
mg at age 60 years (Schroeder & Tipton, 1968). United Kingdom
post-mortem studies have revealed mean total body burdens of 162 mg in
males and 113 mg in females. Studies in the United States of America
have revealed that soft tissue levels also gradually increase with age
in contrast to India, the Far East and Africa, indicating that the
absorption of lead was greater than the capacity of the body to
excrete it. There is no direct evidence that the existing levels of
total body burden from food and air are harmful, but the Committee
felt that this body burden should not be allowed to increase further.
It is virtually impossible to effect a significant reduction in the
total dietary intake arising from naturally occurring lead in food.
The Committee made estimates of the lead intake and body burden from
this source and related this estimate to the total lead intake for
rural and urban environments. This total intake was thought not to
exceed a maximum of 0.45 mg lead per day.
The Committee recognized that for any environmental situation the
hazard to infants and children may be proportionally higher than that
for an adult, because (a) the higher metabolic rate would entail the
inhalation of two to three times the amount of given air pollutant, on
the basis of body-weight; (0 the average dietary lead intake, based on
a dose per kilogram body-weight, would be considerably higher (400 µg
lead per day for a 60 kg adult, versus 130 µg lead per day for a 10 kg
child), and (c) possibly greater absorption from the gastrointestinal
tract would lead to a higher body burden of lead, although definitive
human evidence on this point is lacking.
The Comittee was also aware that nutritional deficiencies could
possibly increase lead absorption rates and under these circumstances
a special assessment would be required.
The Comittee decided that in arriving at a provisional tolerable
weekly intake, use could be made of an estimated level of absorption
from all sources of 1 µg/kg body-weight/day. This would result in the
average adult in a total absorbed amount of lead of about 60-70 µg, of
which the fraction absorbed from air could reach 20 µg, leaving up to
10 µg to be contributed by water and up to 40 µg by food. The
Committee established in adults, on the assumption that only 10% of
lead ingested from food and water is absorbed, a provisional tolerable
weekly intake of 3 mg of lead per person, equivalent to 0.05 mg/kg
body-weight. This level does not apply to infants and children. Any
increase in the amount of lead derived from drinking-water or inhaled
from the atmosphere will reduce the amount that can be tolerated in
food. The lead in air is probably the contribution that is most
accessible to action for reducing the total body burden of lead,
especially where this fraction is large compared with that absorbed
from food.
The Committee recognized the provisional nature of this estimate, and
that for some populations the levels suggested might be exceeded in
practice, because of local conditions. They felt that this
represented no hazard in the short term, but the body load of lead
should be reduced in the long term.
REFERENCES
Anon., (1966) Lancet, i, 1307
Beritic, T. & Vandekar, M. (1956) Blood, 2, 114
Biscaldi, G. P., Robustelli della Cuna, C. & Pollini, G. (1969) Lavoro
Umano, 21, 385, (abstract 363, "The Kettering Abstracts")
Blanksma, L. A., Sachs, H. K., Murray, E. F. & O'Connell, M. J. (1969)
ASCP Meeting, Los Angeles 28 February 1969
Brit. med. J., (1968) Statement 23 November 1968, p. 501
Brit. std. Spec. (1964) 3788, Tin Coated Finish for Colinary Utensils
Bruin, A. (de) & Hoolboom, H. (1967) Brit. J. industr. Med., 24, 203
Butt, E. M. (1960) Metalbinding in Medicine, Martin, J. S., ed.,
Lippincott Co., Philadelphia
Catton, M. J., Harrison, M. J. G., Fullerton, P. M. & Kazantzis, G.
(1970) Brit. mod. J., 2, 80
Cheftel, H. (1950) Ann. Fals. Fraud., 43, 230
Chisolm, J. J. jr (1971) Sci. Amer., 224 (2), 15 (February)
Chisolm, J. J. jr & Kaplan, E. (1968) J. Pediat., 73, 942
Chow, T. J. & Earl, J. L. (1970) Science, 169, 557
Cramér, K. & Dahlberg, L. (1966) Brit. J. industr. Med., 23, 101
Cramér, K. & Selander, S. (1965) Brit. J. industr. Med., 22, 311
Dingwall-Fordyce, I. & Lane, R. E. (1963) Brit. J. industr. Med., 20,
313
Dinischiotu, G. T., Nestorescu, B., Radulescu, I. G., Ioneseu, G.,
Preda, N. & Ilutza, G. (1960) Brit, J. industr. Med., 17, 141
Egan, H. (1972) Conference on lead in the Environment, London
27 January 1972
Emmerson. B. T., (1965) Aust. Ann. Med., 14, 295
FAO/WHO FAO/WHO (1967) Specifications for the Identity and Purity of
Food Additives and their Toxicological Evaluation: Some Emulsifiers
and Stabilizers and Certain Other Substances: Tenth Report, FAO
Nutrition Meetings Report Series, 1967, No. 43; Wld Hlth Org. techn.
Rep. Ser., 1967, No. 373
Fleming, A. J. (1964) Arch. Environ. Hlth., 8, 265
Gibson, Gibson, L. M., Mackenzie, J. G. & Goldberg, A. (1968) Brit. J.
industr. Med., 25, 40
Goldberg, L. (1972) Personal communication to WHO
Goldsmith, J. R, & Hexter, A. C. (1967) Science, 158, 132
Gordon, N., King. E. & MacKay, R. I. (1967) Brit.med. J., 2, 480
Greenfield, I. (1957) N.Y. State J. Med., 57, 4032
Gusev, I. M. (1960) Limits of Concentrations. Book No. 4
Haas, T.Haas, T., Wiech, A. G., Schaller, K. H., Mache, K. & Valentin,
H. (1972) Zbl. Bakt. Hyg., I. Abt. Orig. B 155, 341
Haley, T. J. (1966) Arch. Environ. Hlth., 12, 781
Hernberg, S. & Nikkanen, J. (1970) Lancet, i, 63
Howells, G. P. (1967) Int. Cmttee on Radiol. Protection, draft report
Hunt, W. F. (1970) Chem. Eng. News. June 29, p. 37
Hursh, J. B., Schraub, A., Sattler, E. L. & Hofmann, H. P. (1969) Hlth
Phys., 16, 257
IARC (1972) Monograph on the Evaluation of Carcinogenic Risk of
Chemicals to Man, Vol. 1.
Imamura, Y. (1957) Osaka City Mod. J., 3, 167
IUPAC Inform. Bull. Append. (1965) 10, 71
Kehoe, R. A. (1964) Arch. Environ. Hlth, 8, 232
Kehoe, R. A. (1965) USPHS, Public. No. 1440, 51, Washington
Kehoe, R. A. (1961) Roy. Inst. Publ. Hlth Hyg. J., 24, 101
Kehoe, R. A., Cholak, J. & Story, R. V. (1940) J. Nutr., 12, 579
King, B. G. (1971) Amer. J. His. Child., 122, 337
Klein, M., Namer, R., Harpur, E. & Corbin, R. (1970) New Engl. J.
Med., 283, 669
Kospito, L., Byers, R. K, & Shwachman, H. (1967) New Engl. J. Med.,
276, 949
Kostial, K., Simonovic, I. & Pisonic, M. (1971) Envir. Res., 4, 360
Lawther, P. J., Commins, B. T., Ellison, J. M. & Biles, B. (1972)
Conference on lead in the environment
Lewis, H. K. (1966) USPHS, Public. No. 1441, 18, Washington
Lilis, P., Gavrileseu, N., Nestorescu, B., Dumitriu, C. & Roventa, A.,
(1968) Brit. J. Industr. Med., 25, 196
Lin-Fu, J. S. (1970) Pediatrics, 45, 720
Ludwig, J. H., Diggs, D. R., Hesselberg, H. E. & Maga J. A. (1965)
Amer. industr. Hyg. Ass. J., 26, 270
Mehani, S. (1966) Brit. J. industr. Med., 23, 112
Miettinen, J, K. (1972) Unpublished report to WHO
Moncrieff, A. A., Koumides, O. P., Clayton, B. E., Patrick A. D.,
Renwick, A. G. C. & Roberts, G. E. (1964) Arch. Dis. Childh., 39, 1
Monier-Williams, G. M. (1949) Trace Elements in Foods, Chapman & Hall,
London
Morgan, J. M., Marshall, W. H. & Miller, R. E. (1966) Arch. Intern.
Med., 118, 17
Motto, H. L., Daines, R. N., Chilko, D. M. & Motto, C. K. (1970)
Environm. Sci. Technol., 4, 231
Palmisano, P. A., Sneed, R. C. & Cassady, G. (1969) J. Pediat., 75,
869
Power, J. G. P., Barnes, R. M., Nash, W. N. C. & Robinson, J. D.
(1969) Brit. med. J., 3, 336
Radosevic, Z., Saric, M., Beritic, T. & Knezevic, J. (1961) Brit. J.
Industr, Med., 18, 222
Sandstead, H. H., Brill, A. B., Arias, L., Terry, R. T. & Tinnell, L.
E. (1966) Fed. Proc., 25, 688 (Abstr. No. 2820)
Schroeder, H. A. & Balassa, J. J. (1961) J. Chron. Dis., 14, 408
Schroeder, H. A. & Tipton, I. H. (1968) Arch. Environ. Hlth., 17, 965
Schroeder, H. A., Mitchener, M. & Nason, A. P. (1970) J. Nutr., 100,
59
Schwanitz, G., Lehnert, G. & Gebhart E. (1970) Dtsch. med. Wschr., 95,
1636
Shibko, S. 1. (1972) Personal communication to WHO
Shy, C. M., Hammer, D. I., Newill, V. A. & Nelson, W. C. (1971)
Health Hazards of environmental lead, US Environmental Protection
Agency, Bureau of Air Pollution Sciences, Community Research Branch
Simpson, J. A., Seaton, D. A. & Adams, J. F. (1964) J. Neurol.
Neurosurg. Psychiat., 27, 536
Tepper, L. B. (1963) Arch. Environ. Hlth., 7, 76
United Kingdom Report (1972) Survey of lead in food, Ministry of
Agriculture, Fisheries and Food, H.M.S.O. 1972
United States Public Health Service (1965) Publication No. 999-AP-12
Survey of lead in the Atmosphere of 3 unknown communities
Van Esch, G. J., Van Genderen, H. & Vink, H. H. (1962) Brit. J.
Cancer, 16, 289
Waldron, H. A. (1966) Brit. J. industr. Med., 23, 83
Waller, R. E., Commins, B, T. & Lawther, P. J. (1965) Brit. J.
industr. Med., 22, 128
Walls, A. D. F. (1969) Brit. med. J., 1, 98
Weller, C. V. (1915) J. Med, Res. 33, 271
Wettenberg, L. (1966) Lancet, 1, 498
WHO (1965) Occup. Hlth Report No. 66
WHO (1971) International standards for drinking-water, 3rd ed.
See Also:
Toxicological Abbreviations
Lead (EHC 3, 1977)
Lead (ICSC)
Lead (WHO Food Additives Series 13)
Lead (WHO Food Additives Series 21)
Lead (WHO Food Additives Series 44)
LEAD (JECFA Evaluation)
Lead (UKPID)