EVALUATION OF A TWO-GENERATION REPRODUCTION TOXICITY STUDY ADDING ENDOPOINTS TO DETECT ENDOCRINE DISRUPTING ACTIVITY USING LINDANE

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A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using lindane by dietary administration at 0, 10, 60, and 300 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). F1 offspring were examined for emotionality (open field test), motor coordination (rotarod test), as well as learning and memory (pole-climbing test). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed general toxicological effects on parental animals, influence on reproductive function, and altered development of offspring; however, they did not demonstrate any distinct changes in the extra endpoints for detection of endocrine disrupting activity. Adult toxicity was observed in both F0 and F1 animals, including suppressed body weight gain and reduced food consumption in both sexes, and deaths of females at 300 ppm. Convulsions and irritability were observed during the perinatal period in pregnant F1 females given 300 ppm. Pathological examination revealed increased liver weights and centrilobular hepatocellular hypertrophy in both sexes and generations at 10 or 60 ppm and above; in addition, increased kidney weights and increased hyaline droplets in the proximal tubule epithelium, and basophilic renal tubules in males were noted at 10 ppm and above. Pituitary weights were decreased in F0 females and in F1 males and females and adrenal weights were increased in F1 males and females at 300 ppm; however, no histological changes were observed, and manifestations suggesting endocrine disrupting activity related to these changes were lacking. Hypertrophy of the thyroid follicular epithelium in F0 females at 300 ppm and in F1 males at 60 and 300 ppm, and decreases in T3 and/or T4 in both sexes and generations at 300 ppm were presumed to be secondary changes associated with the induction of hepatic drug-metabolizing enzymes. Blood hormone analysis revealed no changes in sex hormones attributable to lindane in males or females. Hepatic drug-metabolizing enzyme activities were increased dose-dependently from 10 ppm in both sexes and generations, with the rise in BROD activity being the most prominent. There were also increases in MROD, EROD, T-6β-OH, and T4-UDP-GT activities (BROD >> EROD > MROD, T-6β-OH, T4-UDP-GT). This suggests that while lindane most strongly induces CYP2B, it also upregulates a number of other drug metabolizing enzymes, such as CYP1A, CYP3A, and UDP-GT. As for effects on reproductive function, lack of maternal behavior, including lactation and retrieval behavior, and consequent total litter loss were observed in F1 dams at 300 ppm. There were no effects of lindane on the estrous cycle, spermatogenesis, mating, fertility, pregnancy, or parturition. Neonatal toxicity was observed in both sexes and generations, including suppressed body weight gain at 60 and 300 ppm, and decreased thymus and spleen weights without histological change at 300 ppm. The postnatal survival rate in F2 offspring was decreased due to lack of maternal behavior in dams at 300 ppm. Post-weaning examination of F1 offspring revealed minor body weight-related delays in sexual maturation (vaginal opening and preputial separation) in both sexes at 300 ppm. Behavioral tests in F1 animals revealed no obvious changes in emotionality, motor coordination, or learning and memory. No changes in AGO or nipple development were found in either sex or generation. In conclusion, no distinct changes were found in any of the extra endpoints for detection of endocrine disrupting activity even at doses at which severe toxicity was manifested, including death. The fact that endocrine disrupting activity of lindane is very weak, may explain the lack of relevant adverse effects. Further study of chemicals, which have more definite endocrine disrupting activity, is thus necessary to establish the validity of the test method. On the other hand, effects of lindane on development and reproductive function of the succeeding generation, which were not elucidated in a past standard reproduction toxicity study conducted with 100 ppm as the highest dose, were detected with administration ,at 300 ppm. This suggests that reproductive and developmental toxicity can be reliably detected by establishing appropriate doses in two-generation reproduction toxicity studies. This work was conducted as part of a project of the Ministry of Environment, though this paper does not contain any opinions of the Ministry.
日本トキシコロジー学会の論文
2006-02-22

EVALUATION OF A TWO-GENERATION REPRODUCTION TOXICITY STUDY ADDING ENDOPOINTS TO DETECT ENDOCRINE DISRUPTING ACTIVITY USING LINDANE

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