Toxicokinetics - trdoer40211

with estradiol for binding the estrogen receptors in rat uterine cytosol and

estrogen receptors in mammary tumors (Klaassen, Amdur, and Doull 1986).

Depressed sperm counts may accompany excessive absorption of

organochlorines. Aldrin and dieldrin have been reported to produce various

effects on reproduction in a variety of species, such as decreased fertility and

decreased viability of the young, thought to be related to hormonal imbalance

(Klaassen, Amdur, and Doull 1986).

IARC has listed some of these agents as "probably carcinogenic to

humans"(B2), although it also categorizes them as being inadequately assessed

for human carcinogenic potential. Their carcinogenicity has been demonstrated

in animal studies, but insufficient data exist from human studies. Organochlorine

compounds are categorized by carcinogenicity below (IRIS 1997).

Noncarcinogenic Organochlorines

Carcinogenic Organochlorines

Aldrin

delta-BHC

alpha-BHC

Endosulfan I

beta-BHC

Endosulfan II

Lindane

Endosulfan Sulfate

Chlordane

Endrin

DDT, DDE, DDD

Methoxychlor

Dieldrin

Heptachlor

Toxicokinetics

Organochlorines are absorbed by the respiratory tract, skin, and

gastrointestinal tract. The limited dermal absorption of DDT is significantly

enhanced when dissolved in oils, fats, or lipid solvents. DDT and a major

metabolic product, DDE, tend to accumulate in adipose tissue, eventually

reaching equilibrium at a constant rate of intake. There is a close correspondence

between lipid content of organs and concentration of DDT, DDE, and dieldrin in

blood, kidney, liver, and adipose tissue (Klaassen, Amdur, and Doull 1986).

Storage in fat is a type of detoxification, because it decreases the amount of

chemical at the site of toxic action, the CNS. Following absorption in mammals,

the metabolism of DDT includes dehydrochlorination to unsaturated DDE and

substitution of hydrogen for chlorine yielding DDD (Klaassen, Amdur, and

Doull 1986). Following exposures, DDT is slowly eliminated from the body at a

rate of approximately 1 percent of stored DDT excreted per day (Klaassen,

Amdur, and Doull 1986). DDT metabolites (DDD and DDE) are excreted

primarily in urine and feces, and in breastmilk.

The more rapid metabolism of methoxychlor is achieved by O-demethylation

and subsequent conjugation and excretion, catalyzed by microsomal enzymes in

mammals (Klaassen, Amdur, and Doull 1986). Aldrin and heptachlor are

metabolized by microsomal enzymes to their corresponding epoxides, and they

can be equally or more toxic than the corresponding parent compound (Klaassen,

Amdur, and Doull 1986). Therefore, the epoxide formation might be considered

an activation reaction. These epoxides are stored in the adipose tissues of

D59

Appendix D Toxicological Profiles