was published in 1993 (NAS, 1993). Among the recommenand evaluated for changes to the immune system and for reproducdations were changes in the risk assessment process, changes tive toxicity. Dose-dependent amounts of MXC and metabolites were present in milk and plasma of dams and pups. The high dose in surveillance of the food supply, and a call for better inforof MXC reduced litter size by É17%. Ano-genital distance was mation on the effects of pesticides on the developing aniunchanged, although vaginal opening was accelerated in all mals' reproductive, immune, and central nervous systems. treated groups, and male prepuce separation was delayed at the The National Toxicology Program, in conjunction with middle and high doses by 8 and 34 days, respectively. In the collaborators at EPA's National Health and Environmental neurobehavioral evaluation, high-dose males were more excitable, Effects Research Laboratory, developed a design that would but other changes were inconsistent and insubstantial. A decrease address some of the data needs identified in the NAS report. in the antibody plaque-forming cell response was seen in malesThe NAS report identified the exposure period of concern only. Adult estrous cyclicity was disrupted at 50 and 150MXC, for humans as being from the last trimester of pregnancy to doses which also showed reduced rates of pregnancy and delivery. years of age, a range that is approximated in the rodentUterine weights (corrected for pregnancy) were reduced in all study used here. Because the concern was on direct contreated pregnant females. High-dose males impregnated fewer untreated females; epididymal sperm count and testis weight were sumption of pesticide residues, we dosed dams for the week before and the week after birth, and then direct-dosed the pups from postnatal day (pnd)7 to pnd42, the approximate This article has been reviewed by the National Health and Environmental age of puberty in these rats. Animals are taken at various Effects Laboratory, U.S. Environmental Protection Agency, and approved points in the dosing period to ascertain effects: compound for publication. Approval does not signify that the contents necessarily in milk is determined at pnd7, the last day of dosing for the reflect the views of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.dam, and the time during her dosing when she is likely to 138
In order to address data gaps identified by the NAS report Pesticides in the Diets of Infants and Children, a study was performed using methoxychlor (MXC). Female rats were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week before and the week after birth, whereupon the pups were directly dosed with MXC from postnatal day (pnd) 7. Some dams were killed pnd7 and milk and plasma were assayed for MXC and metabolites. For one cohort of juveniles, treatment stopped at pnd21; a modified functional observational battery was used to assess neurobehavioral changes. Other cohorts of juveniles were dosed until pnd42 and evaluated for changes to the immune system and for reproductive toxicity. Dose-dependent amounts of MXC and metabolites were present in milk and plasma of dams and pups. The high dose of MXC reduced litter size by approximately 17%. Ano-genital distance was unchanged, although vaginal opening was accelerated in all treated groups, and male prepuce separation was delayed at the middle and high doses by 8 and 34 days, respectively. In the neurobehavioral evaluation, high-dose males were more excitable, but other changes were inconsistent and insubstantial. A decrease in the antibody plaque-forming cell response was seen in males only. Adult estrous cyclicity was disrupted at 50 and 150 MXC, doses which also showed reduced rates of pregnancy and delivery. Uterine weights (corrected for pregnancy) were reduced in all treated pregnant females. High-dose males impregnated fewer untreated females; epididymal sperm count and testis weight were reduced at the high, or top two, doses, respectively. All groups of treated females showed uterine dysplasias and less mammary alveolar development; estrous levels of follicle stimulating hormone were lower in all treated groups, and estrus progesterone levels were lower at 50 and 150 MXC, attributed to fewer corpora lutea secondary to ovulation defects. These data collectively show that the primary adult effects of early exposure to MXC are reproductive, show that 5 mg/kg/day is not a NO(A)EL in rats with this exposure paradigm (based on changes in day of vaginal opening, pubertal ovary weights, adult uterine and seminal vesicle weights, and female hormone data) and imply that the sites of action are both central and peripheral.
1. The major pathways of ethoxyquin (EQ) metabolism in both the rat and mouse are O-deethylation and conjugation to endogenous substrates. 2. The two major EQ-derived metabolites excreted in rat urine were in the form of sulphate conjugates, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate, and 1,2,3,4-tetrahydro-3,6-dihydroxy-4-methylene-2,2-dimethylquinoline sulphate. The latter apparently arises from an intramolecular rearrangement of the 3,4-epoxide of ethoxyquin. 3. Mouse urine contained one major glucuronide, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline glucuronide as well as one major sulphate conjugate, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate. 4. EQ-derived radioactivity was excreted in rat bile, mainly as GSH conjugates, with little unchanged EQ present. Two of the biliary metabolites are glutathione conjugates of ethoxyquin 3,4-epoxide; the third appears to be a conjugate of either ethoxyquin 7,8-epoxide or 2,2,4-trimethylquinol-6-one.
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