BHC (TECHNICAL) JMPR 1973
Explanation
BHC technical was reviewed previously by the Joint Meeting
(FAO/WHO, 1969). The 1968 Joint Meeting did not recommend an ADI
because technical HCH was not standardized as to its composition of
various isomers of differing toxicological potency and action, and
because of lack of adequate toxicological data on the different
isomers. It was recommended that before an ADI could be established
additional toxicological data of the following nature was necessary:
short- and long-term feeding studies and a reproduction study on
individual isomers and commonly marketed technical products, metabolic
studies of isomers in animals, determination of effects on liver
microsomal enzymes and interactions of isomers of HCH and residue
levels in tissues.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Biochemical aspects
A single oral dose of 200 mg/kg of BHC enhanced the metabolism of
pentetrazol by rat liver homogenates in vitro and hastened the
disappearance of this drug in vivo when the BHC was given four days
prior to pentetrazol treatment (Vohland and Koransky, 1972a, b).
Liver growth inducing action of single doses of 200 and 400 mg/kg
(p.o.) of BHC in rats has been confirmed. This was due both to
increased numbers and volume of hepatocytes. Although liver weight had
returned to normal by four weeks after administration, liver DNA and
number of cell nuclei remained above control values
(Shulte-Hevmenetol, 1971).
In rats administered BHC technical at 50 mg/kg for 7 days the
order of accumulation of isomers was beta > alpha > gamma > delta;
the order of excretion in urine was alpha > gamma > delta > beta;
and the duration of excretion was beta > alpha > gamma > delta.
The beta isomer was found not only in livers of rats treated with
this isomer but also in livers of rats given the other isomers
indicating possible isomerization (Katama, 1971). Following oral
administration to rabbits for 14 days antibodies against DDT and BHC
were found more frequently than against organophosphates six months
after discontinuation of exposure (Nikolayev and Usmanova, 1971).
Morphological changes in nasal mucous membrane of rabbits were
investigated during oral administration of BHC at 1 mg/kg/day. After
40-50 days mucosal dystrophy advances to catarrhal rhinitis and
further degenerative changes (Sadriyeva et al., 1971).
A substantial effect of beta-BHC on mice fetal development was
observed following s.c. or oral administration to pregnant mice at
various stages of gestation. The translocation of beta-BHC from
mother to fetus was estimated to be 1/5-1/8 of the residue observed
in the mother (Yamagishi et al., 1972).
TOXICOLOGICAL STUDIES
Short-term studies
Mouse
Male mice (20/group) were fed diets containing 0, 6.6, 66 and 660
ppm BHC (technical) for 24 weeks. The mixture consisted of the
following percentage composition of isomers alpha - 67%, beta - 11%,
gamma - 15%, delta - 6.4% and others 0.6%. At the end of 24 weeks,
the mice were killed and examined grossly and histologically. All
mice in the 660 ppm group had liver "tumors", their liver weights
were 3.7 times those of control, and the livers had a rough surface
with many large, yellowish nodules up to 1.0 cm in diameter.
Microscopic examination showed the nodules to be hepatomas. No
remarkable changes were seen in the controls or in the 6.6 and 66 ppm
groups (Nagasaki et al., 1971a, b).
In a subsequent investigation 12 groups of 20 mice were fed one
of the following diets: basal diet (controls) or 500, 250 or 100 ppm
of each of the alpha, beta, gamma and delta isomers of BHC. The
animals were killed and examined after 24 weeks of feeding as above.
Hepatomas were observed in all the animals fed 500 ppm of the
alpha-isomer and in nine animals fed 250 ppm of the alpha-isomer,
none of the other groups had hepatomas. The authors concluded that
the alpha-isomer was probably responsible for the hepatomas produced
by the crude HCH that was used in the first experiment (Nagasaki et
al., 1972a).
The residual accumulation of alpha-BHC in the 500 ppm dosed group
was 11.44 ppm and beta was 12.37 ppm (Tomii et al., 1972). In a
continuing study, rats were fed BHC technical and various isomers at
0, 250, 500 and 1000 ppm for 24 and 48 weeks. Increased liver weight
was observed only at 500 ppm and above after 24 weeks. At 48 weeks one
of seven rats fed alpha BHC at 1000 ppm developed a hepatoma while
three others showed hypertrophic nodules without signs of malignancy.
No BHC induced hepatomas were reported. It was concluded, alpha-BHC
is considered to have carcinogenicity potential in the liver and rats
are less sensitive than mice (Nagasaki et al., 1972b).
BHC (technical) and the individual isomers were fed to CR-JC
strain mice at dose levels of 0 and 600 ppm for six months. Livers
were significantly overweight at 26 weeks with hepatomas observed in
all treated mice. A high incidence of malignant hepatomas were noted
in the groups fed the pure isomers only. These authors conclude that
the alpha isomer or a metabolite is the most carcinogenic (Goto et
al., 1972a, b).
Observations in man
Although low concentrations of all four of the primary isomers of
HCH have been detected in human tissues or body fluids, the
beta-isomer is found most frequently and at highest concentration.
Analyses of human milk from women in 24 prefectures in Japan revealed
average residues of 0.150 ppm in town residents and 0.105 ppm in
country residents. Depending upon the prefecture, average values
ranged up to 0.4 ppm. beta-HCH residues in human milk far exceed the
residues of DDT and dieldrin (Tanabe, 1972). In man the
concentrations of the isomers, in decreasing order, was beta >
alpha > gamma > delta (Tatsukawa et al., 1972).
Comments
The 1968 Joint Meeting did not recommend an ADI because technical
BHC was not standardized as to its composition of various isomers of
different toxicological potency and activity. Although certain data
are available on persistence of the isomers, there was a lack of
adequate toxicological data on other isomers. It was recommended that
before an ADT could be established additional toxicological data of
the following nature were necessary: short- and long-term feeding
studies and a reproduction study on individual isomers and commonly
marketed technical products, metabolic studies of isomers in animals,
determination of effects on liver microsomal enzymes and interactions
of isomers of BHC and residue levels in tissues.
Essentially no new data of the type requested have been
submitted. The Meeting, therefore, concluded that there is still
insufficient information for an evaluation of the potential health
injurious effects of technical BHC. The demonstration of hepatoma
production in mice by feeding 500 and 250 ppm of the alpha-isomer, the
major constituent of technical BHC for only 24 weeks was regarded as a
matter for concern. In other studies the beta and alpha-isomer have
also been demonstrated to produce hepatoma in mice at levels of 200
and 400 ppm in the diet, respectively.
TOXICOLOGICAL EVALUATION
There is insufficient information to estimate a no-effect level
and hence, no ADI can be recommended. Additionally the beta-isomer
is quite persistent in the environment and frequently occurs in
human fat and blood.
RESIDUES IN FOOD AND THEIR EVALUATION
Appraisal
Residues of technical BHC are widely distributed throughout the
world's food supply, especially in meat and milk. They appear
regularly in total diet studies in the United States of America
(Duggan, 1972), Canada (Smith et al., 1973) and Czechoslovakia as well
as in commodity surveys (occasionally at high levels) in Japan (milk,
milk products, fish, imported meat) (Minigawa et al., 1972; Otsuki et
al., 1972; Sakai et al., 1972; Takeda et al., 1972), Czechoslovakia
(milk fat) (Rosa, 1973), France (animal feed, milk) (Marion, 1973),
India (green leafy vegetables) (Viswerwariah and Jayaram, 1972) and
Great Britain (imported cereals, nuts forage, pulses) (Hill, 1973;
Macherbe, 1973).
This insecticide was first evaluated in 1968 at which time no
recommendations for tolerances could be made due to lack of data on
results from supervised trials, on the composition of the technical
product, or on the nature of the terminal residues. At this
re-evaluation there were no data available on residues resulting from
supervised trials on agricultural crops or animals (other than from
the grazing of sheep on treated pasture), therefore no tolerances or
practical residue limits could be recommended.
RECOMMENDATIONS
As the insecticidal activity of technical BHC is accounted for by
its content of the gamma isomer and as the gamma isomer is disposed of
more rapidly by animals and is generally less persistent in the
environment than the alpha and beta isomers, which are the isomers
found most widely in food intake studies, every encouragement should
be given to the replacement of technical BHC by lindane (99% gamma
BHC) or alternative pesticides wherever possible.
FURTHER WORK OR INFORMATION
Required (before an acceptable daily intake can be established and
before residue limits can be recommended)
1. Additional chronic feeding studies appropriately designed
to detect carcinogenic action. The studies should be carried out
on all isomers if possible, but at least on the alpha-isomer and
a typical technical mixture. A species other than the mouse would
be appropriate.
2. Further comparative studies of the effects of the four
primary isomers on reproduction, including teratogenicity.
3. The composition of BHC (technical) available and in use
in various countries.
4. The uses made of these technical products, particularly
the rates and frequencies of application and the identities of
the crops involved.
5. The levels of the residues of the individual isomers
found in plants, animals, and their products.
Desirable
1. Studies to establish the extent to which one isomer may
alter the action or storage of another isomer.
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See Also:
Toxicological Abbreviations