Two-generation reproductive toxicity study of inhaled acrylonitrile vapors in Crl:CD(SD) rats.

To assess the effects of acrylonitrile (AN) exposure on reproduction, Sprague-Dawley rats (25/sex/group) were exposed to vapor atmospheres of AN via whole-body inhalation at concentrations of 0, 5, 15, 45 (two offspring generations) and 90 ppm (one offspring generation), 6 h daily, 1 litter/generation, through F2 weanlings on postnatal day 28. After approximately 3 weeks of direct exposure following weaning, exposure of the F1 animals at 90 ppm was terminated due to excessive systemic toxicity in the males. There were no exposure-related mortalities in adult animals, no functional effects on reproduction or effects on reproductive organs, and no evidence of cumulative toxicity or of enhanced toxicity in pregnant and lactating dams or in developing animals. Adult systemic toxicity was limited to body weight and/or food consumption deficits in both sexes and generations (greater in males) at 45 and 90 ppm and increased liver weights in the 90 ppm F0 males and females and 45 ppm F1 males. Neonatal toxicity was expressed by F1 offspring weight decrements at 90 ppm. Clinical signs of local irritation during and immediately following exposure were observed at 90 ppm. Microscopic lesions of the rostral nasal epithelium, representing local site-of-contact irritation, were observed in some animals at 5 to 45 ppm. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity over two generations and neonatal toxicity of AN administered to rats via whole-body inhalation was 45 ppm. The NOAEL for reproduction was 90 ppm for the first generation. The NOAEL for parental systemic toxicity was 15 ppm.

Skin irritation, basal epithelial cell proliferation, and carcinogenicity evaluations of a representative specialty acrylate and methacrylate.

Specialty acrylates and methacrylates (SAM) comprise a large family of industrial monomers. In the late 1980s, the United States EPA and the industry SAM Panel collaborated to evaluate the potential effects, particularly carcinogenesis, of this family of chemicals. As part of this arrangement, the SAM Panel, with EPA input and approval, conducted four studies with a representative acrylate, triethyleneglycol diacrylate (TREGDA), and methacrylate, triethyleneglycol dimethacrylate (TREGDMA). All studies used unoccluded skin application to male mice as follows: Study 1, evaluation of skin irritation compared to cell proliferation in the basal epithelium (BE) following 7 or 14 days of treatment; Study 2, 14-day dose range-finding study; Study 3, 90-day subchronic toxicity study; and Study 4, chronic bioassays employing the EPAs draft guidelines for dermal chronic bioassays. BE cell proliferation was determined in subchronic and carcinogenicity studies (Studies 1, 3, and 4). Organ weight changes (Studies 3 and 4) and increased mortality (Study 4) were observed for the highest dose of TREGDMA. However, there was no related histopathology. Both chemicals induced cell proliferation (7 days through 78 weeks) that correlated with acute and chronic inflammation of the skin. No skin tumors were observed in this study. TREGDA resulted in skin lesions at doses approximately 20-fold lower than TREGDMA. Most of the skin lesions showed similar patterns of microscopic cutaneous alteration suggestive of nonspecific irritation for both chemicals. However, the high concentration TREGDA group in the 78-week study also had evidence of epidermal cell necrosis. In contrast to earlier studies with acrylates, dose selection was based on careful examination of skin irritation and cell proliferation to avoid excessive skin damage. Under these conditions, TREGDA and TREGDMA were not carcinogenic.

Comparison of the developmental and reproductive toxicity of diethylstilbestrol administered to rats in utero, lactationally, preweaning, or postweaning.

The objective of the study was to determine which period of exposure produces the most marked effects on the reproductive capacity and sexual development of the rat, with particular emphasis on the relative sensitivity of in utero and postnatal exposures. The endocrine active chemical, diethylstilbestrol (DES) was used as an agent known to affect many of the endpoints examined. Hitherto, such comparisons have been made between studies, rather than within a study. Our data will be helpful in the interpretation of future multigenerational assay data. In preliminary studies, DES was shown to be active in the immature rat uterotrophic assay with a lowest detected dose of 0.05 mg DES/kg body weight by sc injection and 10 mg DES/l (1.6 mg DES/kg body weight) by administration in drinking water. A dose of 60 microg DES/l drinking water ( approximately 6.5mg DES/kg body weight/day) was selected for the main study since this represented the midpoint of the drinking water uterotrophic dose response and produced no overt maternal toxicity. The study used 10 groups of concomitantly pregnant animals, including 2 control groups. The first comparison was between the effects of exposure to DES in utero, and exposure from conception to weaning. Another group of animals was exposed to DES in utero and cross-fostered to untreated pregnant females to prevent lactational transfer of DES to pups. Two groups were exposed to DES neonatally, either from birth to postnatal day (PND) 10 (pups thus having only lactational exposure), or from birth until weaning (PND 21; pups thus having both lactational exposure and self-exposure via drinking water). In addition, a dose response study to DES was conducted on animals exposed from weaning to PND 100, when the first phase of the study was terminated. Pups exposed to DES in utero and pups exposed from weaning to PND 100 were bred to assess fertility of the F1 animals and the sexual development of F2 offspring. This last comparison was to determine the extent to which weanling rats could be used in endocrine toxicity studies to assess their potential to show activity in utero. The most sensitive period of exposure for inducing developmental effects in F1 animals was from weaning onwards. The neonatal to weaning period (PND 1-21) was the next most sensitive. Essentially no effects were induced in F1 animals exposed in utero. No effects of any kind were observed in animals only exposed over the early neonatal period of PND 1-10. The mean day of vaginal opening, testes descent, and prepuce separation was only altered in groups where postnatal exposure to DES continued beyond PND 10, or was started at weaning. No changes were observed in anogenital distance or caudal sperm counts. Some changes in organ weights were observed, but the interpretation of these was often confused by concomitant changes in body weight. In general, histopathological examination of tissues yielded no additional information. In breeding studies with animals exposed to DES in utero, or from weaning, reduced litter sizes and marginal advances in the day of vaginal opening were observed in the offspring, together with changes in organ weights. However, no unique sensitivity was noted for exposure in utero. Evaluation of the several exposure periods and the many markers monitored in this study may have individual strengths in individual cases, but when rigorously compared using the reference estrogen DES, many preconceptions regarding their absolute or relative value were not upheld. Further, each of these markers is subject to natural variability, as demonstrated by comparisons made among the 5 separate control groups available in parts of the present study. This variability increases the chance that small changes observed in endocrine toxicity studies employing small group sizes and a single control group, or no concomitant control group, may be artifactual. The most marked effects observed in this study were on the developmental landmarks in the F1 animals induced by exposures after PND 10. Some effects on developmental landmarks and organ weights were observed in F2 animals following exposure either in utero or postweaning. This study therefore does not establish a unique role for exposures in utero or during the early neonatal period.

Subchronic peroral toxicity of triethylene glycol in the Fischer 344 rat.

Ethylene and diethylene glycols produce systemic toxicity, including nephrotoxicity, by acute and repeated po dosing. To determine the potential for triethylene glycol (TEG; CAS Number 112-27-61) to produce nephrotoxicity, or other organ/tissue injury, a subchronic (90-d) study was conducted by continuous inclusion of TEG in the diet of Fischer 344 rats. This was preceded by a probe 14-d study. For both studies the dietary concentrations were 0 ppm (control), 10,000, 20,000 or 50,000 ppm TEG, resulting in daily TEG consumptions in the 14-d study of 1132, 2311 or 5916 mg/kg with males, and 1177, 2411 or 6209 mg/kg with females. The corresponding values for the 90-d study were 748, 1522 or 3849 mg/kg (males), and 848, 1699 or 4360 mg/kg (females). In the 14-d study there were no mortalities or clinical signs, and no effects on body weight, hematology, serum chemistry, organ weights, and gross or microscopic pathology. Food consumption was increased at the high dosage. Urinalysis showed increased urine volume and decreased pH with high dose males and females, and increased volume with mid-dose males. In the subchronic study there was neither mortality nor signs of toxicity, and no dosage-related effects with serum chemistry, gross and microscopic pathology. Body weights were reduced during the dosing period with both males and females of the high dosage. Body weight gains were reduced at all dosages with males and females. No hematological effects were seen with females, but males of the mid- and high-dosage groups had slightly reduced erythrocyte count and hematocrit, and high-dose males had decreased hemoglobin concentration with increased mean corpuscular volume. These were considered to reflect a mild hemodilution related to the absorption of large TEG doses. Urinalysis showed dosage-related decreased pH, and increased urine volume mainly at the high dose. These were probably related to the renal excretion of absorbed TEG and/or metabolites. Kidney weight was increased for high-dose females, and increased relative (to body) weight of kidneys for males and females from the mid- and high-dose groups were observed, probably related to the renal excretion of the absorbed TEG and/or its metabolites. These findings indicate that the subchronic continuous po dosing of TEG to rats does not result in local or systemic specific organ or tissue toxicity. These findings contrast with the known repeated po toxicity, notably nephrotoxicity, produced by ethylene and diethylene glycols. Thus, TEG has significantly lesser potential for systemic toxicity by the po route than its lower molecular weight homologues.

Effect of rodent diets on the sexual development of the rat.

Five rodent diets have been evaluated for their possible effect on the sexual development of the rat. Groups of 12 pregnant Alpk rats were fed one of the following combinations of diets during pregnancy and postnatally: RM3/RM1, AIN-76A/AIN-76A, RM3/AIN-76A, Teklad Global 2016 (Global)/Global and Purina 5001/Purina 5001. AIN-76A is phytoestrogen-free while the other diets contained varying amounts of phytoestrogens. The phytoestrogens genistein and daidzein were determined in the diets studied, and the concentrations found agreed with earlier estimates. RM3/RM1 was selected as the control group, as this has been used routinely in this laboratory for the past decade. Determinations were made in offspring of the times of vaginal opening and first estrus among the females, and of prepuce separation and testes descent among the males. At postnatal day (PND) 26 the females from 6 of the 12 litters were terminated and tissue weights measured. Males from 6 of the 12 litters were similarly studied at PND 68. Animals from the remaining litters were transferred to RM1 diet at PND 70. Termination of the study was at PND 128 (males) and PND 140 (females) when body weights and tissue weights were determined. Marked differences in body weight, sexual development, and reproductive tissue weights were observed for rats maintained on AIN-76A or Purina 5001, with only minimal effects among rats maintained on the Global diet. These comparisons were against RM3/RM1 as the reference diet. However, using Purina 5001 as the reference diet reversed the direction of the differences seen when using RM3/RM1 as the reference diet. The differences observed when using RM3/RM1 as reference diet occurred mainly postnatally. In addition, the fact that similar differences were seen for the phytoestrogen-free diet, AIN-76A, and the phytoestrogen-rich diet, Purina 5001, indicate that these effects are more likely to be caused by nutritional differences between the diets that then have centrally mediated effects on rodent sexual development, rather than individual dietary components affecting peripheral estrogen receptors (ER). This proposal is supported by abolition of the uterotrophic activity of AIN-76A and Purina 5001 (relative to RM3/RM1) in the immature rat by coadministration of the gonadotrophin-releasing hormone (GnRH) antagonist ANTARELIX: The present data indicate that choice of diet may influence the timing of sexual development in the rat, and consequently, that when evaluating the potential endocrine toxicity of chemicals, the components of rodent diets used should be known, and as far as is possible, controlled.

Comparative in vitro percutaneous absorption of nonylphenol and nonylphenol ethoxylates (NPE-4 and NPE-9) through human, porcine and rat skin.

The purpose of this study was to assess the percutaneous absorption of nonylphenol (NP) and the nonylphenol ethoxylates, NPE-4 and NPE-9, in human, porcine and rat skin. In vitro studies with the NPEs were conducted for 8 h in flowthrough diffusion cells using topical solutions of 0.1, 1.0 and 10% in PEG-400 or 1% in water (NPE-9 only). NP absorption was assessed as a 1% solution in PEG-400. All compounds were 14C ring-labeled and radioactivity in perfusate was monitored over time. Skin deposition was measured at the termination of the experiment. Absorption into perfusate and total penetration (compound absorbed plus compound sequestered in skin) were calculated. Absorption of NPE-4, NPE-9 and NP was similar across all species at less than 1% of the applied dose over 8 h. Penetration was generally below 5% of applied dose, the majority located in the stratum corneum. In all species and for both NPEs, the fraction of dose absorbed was highest for the lowest applied dose. Absorptions expressed as actual mass absorbed over 8 h were similar (approximately 0.3 microg/cm2) across all concentrations. Penetration, but not absorption, was greater from a water vehicle compared to a PEG-400 vehicle, particularly in rat skin. These studies suggest that NP, NPE-4 and NPE-9 were minimally absorbed across skin from all three species. Fractional absorption was concentration-dependent, making the actual absorbed flux constant across all doses.

Effects of p-nonylphenol (NP) and diethylstilboestrol (DES) on the Alderley Park (Alpk) rat: comparison of mammary gland and uterus sensitivity following oral gavage or implanted mini-pumps.

An earlier report by Colerangle and Roy indicated that administration of p-nonylphenol (NP) to Noble rats, via subcutaneously implanted mini-pumps at estimated doses of 53.2 and 0.073 mg kg(-1) day(-1) for 11 days, led to proliferation of the mammary gland. Those results indicated a ca. 600-fold enhancement in assay sensitivity to NP over that of the standard 3-day rat uterotrophic assay. The potential importance of these observations led us to repeat the experiments in the Noble rat, as described earlier. Although our earlier results confirmed the reported effects of diethylstilboestrol (DES) on the mammary gland of Noble rats, we found no effects with NP. The present report extends our investigations of the effects of NP and DES on the mammary gland and uterus of other rat strains using both oral dosing and exposure via mini-pumps. The 3-day oral uterotrophic assay responses to NP were similar for immature Alderly Park (Alpk; Wistar-derived) and immature Sprague-Dawley rats. Likewise, oral administration of NP to ovariectomized Alpk rats for 11 days gave responses of a similar magnitude to those seen in the 3-day immature assays and in earlier 3-and 11-day oral assays conducted using Noble rats. Administration of NP via mini-pumps to ovariectomized Alpk rats, at the implant doses employed by Colerangle and Roy, gave a negative uterotrophic response. The highest achieved dose levels of NP in the implant experiment (27 mg kg(-1) day(-1)) were lower than in the above assays and the negative response was therefore consistent with the previously defined minimum detection level for NP in the uterotrophic assay of ca. 40 mg kg(-1) day(-1) day(-1). It is concluded that the uterotrophic activity of NP is independent of the strain of rat, the duration of dosing and the route of exposure. Two mammary gland studies were conducted on NP and DES in the Alpk rat. In the first study (a repeat of the techniques used in earlier studies with the Noble rat), NP was administered via mini-pumps (achieved doses of 0.052 and 37.4 mg kg(-1) day(-3) NP) and produced no effect on mammary gland development, whereas DES gave the expected trophic response. In the second mammary gland study, NP was administered orally to Alpk rats at 100 mg kg(-1) day(-1) for 11 days (a dose that produced a positive uterotrophic response in ovariectomized rats). In this experiment, DES, and to a lesser extent NP, increased mammary gland differentiation and cell proliferation. The present studies have demonstrated that the rat mammary gland responds predictably to oestrogenic stimulation but does not show increased sensitivity to oestrogens when compared to the rat uterus. It is also concluded that the minimum detection level for oestrogenic responses of NP in rodents, following oral, dietary and implant routes of exposure, is ca. 40 mg kg(-1) day(-1).

Two-generation reproduction study with para-tert-octylphenol in rats.

Octylphenol (OP) is a commercial intermediate used primarily for the production of octylphenol polyethoxylate surfactants. To determine potential reproductive toxicity of OP, a two-generation reproduction study was conducted according to U.S. EPA OPPTS Guideline 870.3800 (draft 1996). Additional measurements were made on retained F2 offspring. OP was administered ad libitum to five groups of rats (30/sex) at dietary concentrations of 0, 0.2, 20, 200, or 2000 ppm. The 0.2 ppm concentration was included to evaluate potential low dose effects. Effects were observed only at 2000 ppm, including decreased body weights in adults and during the latter portion of lactation in offspring and minor body weight-related delays in acquisition of vaginal opening and preputial separation. No effects on reproductive parameters, testes, prostate, or ovary weights or morphology, on sperm counts, motility, morphology, production, or on estrous cyclicity were observed. No estrogen-like effects were evident. The NOAELs for systemic and postnatal toxicity were 200 ppm and at or above 2000 ppm for reproductive toxicity. This study supports the increasing evidence that screening assays for estrogenic activity or studies with limited numbers of animals and/or unrealistic dose regimens are inappropriate for use in the assessment of human health and environmental risk. It does not support previous preliminary data on low dose effects of OP.

Comparative activities of p-nonylphenol and diethylstilbestrol in noble rat mammary gland and uterotrophic assays.

Colerangle and Roy (1996, Endocrine 4, 115-122) have described the apparent ability of both diethylstilbestrol (DES) and p-nonylphenol (NP) to cause extensive cell proliferation and lobular development in the mammary glands of young adult Noble rats. The chemicals were administered over 11 days via subcutaneously implanted minipumps. The dose level of DES used (0.076 mg/kg/day) was about 70 times higher than its minimum detection level in rodent uterotrophic and reproductive toxicology studies. In contrast, the lowest active dose level of NP (0.073 mg/kg/day) in the Noble rat mammary gland study was about 600 times lower than its minimum detection level in rat uterotrophic and multigeneration studies. The apparent enhanced sensitivity of the Noble rat mammary gland to the estrogenic activity of NP was considered worthy of further study. Ovariectomized Noble rat uterotrophic assays with NP (minimum detection level approximately 40 mg/kg/day, 3 or 11 days, oral gavage) revealed similar assay sensitivity to that observed for earlier immature and ovariectomized Alderley Park (AP) rat uterotrophic assays of this chemical. The response of the ovariectomized Noble rat uterotrophic assay to DES and estradiol was also as expected from earlier immature AP rat assays. It is concluded that the general sensitivity to estrogens of the Noble rat and the AP rat is similar. A repeat of the Noble rat mammary gland study with DES (11 x 0.076 mg/kg/day) and NP (11 x either 0.073 or 53.2 mg/kg/day), as originally reported by Colerangle and Roy (1996), revealed a strong positive response to DES and no response to NP. It is concluded that the minimum detection level of NP as a weakly estrogenic material in the rat should be based on the results of rat uterotrophic and multigeneration studies and therefore be set at approximately 40 mg/kg/day. It is also concluded that induced S-phase in the rodent mammary gland is best monitored using BRDU, as opposed to PCNA staining, and that use of subcutaneously implanted minipumps/pellets is inappropriate for risk/hazard assessment studies of chemicals already established as estrogenic in vitro and in vivo, as are NP and DES.

Subchronic toxicity (90-day) study with para-nonylphenol in rats.

As a component to the risk assessment process for para-nonylphenol (NP; CASRN 84852-15-3), a 90-day study was conducted in rats following U.S. EPA TSCA guidelines and Good Laboratory Practice regulations. NP was administered to four groups of rats at dietary concentrations of 0, 200, 650, or 2000 ppm which corresponded to approximate dietary intakes of 0, 15, 50, or 150 mg/kg/day, respectively. There were 25 rats/sex/group in the control and high-dose groups and 15 rats/sex/group in the low- and middose groups. Ten of the 25 rats/sex in the control and high-dose groups were designated as recovery animals and were maintained on control diets for 4 weeks after completion of the 90-day exposure period to assess the reversibility of any effects which might be observed. To evaluate for the possible weak estrogen-like activity that has been reported for NP in a number of screening assays, estrous cyclicity was monitored using vaginal cytology during Week 8 of the study, and sperm count, motility, and morphology were evaluated at termination. In-life effects from NP exposure were limited to small decreases in body weight and food consumption in the 2000-ppm dose group. Postmortem measurements at Week 14 indicated a dose-related kidney weight increase in males and a decrease in renal hyaline globules/droplets in males from the high-dose group. The kidney weights showed complete recovery following the 4-week postdosing recovery period. Due to the small magnitude of the changes (i.e., all weights were within or near laboratory historical control values) and the lack of correlating clinical or histopathological changes, the kidney weight alterations were not considered toxicologically significant. The biological significance of reduced hyaline in the kidneys of male rats from the high-dose group is uncertain. Renal tubular hyaline is associated with the rat-specific protein, alpha-2u-globulin, and, therefore, this finding was not considered toxicologically relevant to humans. No other effects attributable to NP were observed. No changes were observed for estrous cycling, sperm evaluations, or effects on endocrine organs. NP, therefore, did not manifest any estrogen-like activity as measured in these parameters at dietary concentrations as high as 2000 ppm, the maximum dose administered in this study. Based on the minor findings for the 2000-ppm dose group, the NOAEL (no-observed-adverse-effect level) for NP in this study is considered to be 650 ppm in the diet, corresponding to an approximate intake of 50 mg/kg/day.

Effects of diethylenetriamine dihydrochloride following 13 weeks of dietary dosing in Fischer 344 rats.

Fischer 344 rats were fed a diet containing the dihydrochloride salt of diethylenetriamine (DETA.2HCl) at concentrations of 1000, 7500 or 15,000 ppm for 90 consecutive days. Based on food consumption and body weight, the mean corresponding dosages were 70, 530 and 1060 mg/kg/day for the males and 80, 620 and 1210 mg/kg/day for the females. Decreases in food consumption were observed intermittently throughout the dosing period in both sexes at 15,000 ppm. Dose-related decreases in body weight or weight gain were observed for both sexes at 7500 and 15,000 ppm. Changes in clinical pathology measurements observed at 7500 and 15,000 ppm included increases in mean corpuscular volume and mean corpuscular haemoglobin in males, and increases in mean corpuscular volume, total leucocytes and urinary pH, and a decrease in serum glucose concentration in females. The relative kidney, brain and testes weights were increased in the 15,000 ppm males. In the females, the relative kidney, brain and liver weights were increased at 7500 and 15,000 ppm, and the relative heart and adrenal weights were elevated at 15,000 ppm. There were no treatment-related clinical signs, gross autopsy or histopathological findings for either sex at any dose level. Animals improved only slightly from the effects of treatment following a 4-wk recovery period. A no-observable-effect level of 1000 ppm DETA.2HCl in the diet was established in this subchronic toxicity study.

Repeated exposure toxicity of 2-ethyl-1,3-hexanediol by cutaneous applications to the rat for 9 and 90 days.

2-Ethyl-1,3-hexanediol (EHD; CASRN 94-96-2), an industrial chemical and insect repellent, has a high potential for recurrent skin contact. Short-term (9 d) and subchronic (13 w) repeated epicutaneous contact studies were conducted to determine the potential for cumulative local skin irritation and systemic toxicity in Fischer 344 rats. Doses were 0.5, 2.0 or 4.0 ml/kg/d of undiluted EHD. There were no clinical signs and no treatment-related effects on hematology, clinical chemistry or histology of a large number of organs and tissues including the treated skin. The only effects where slight decreases in body weight gain for the high-dose males in the 9-d study and males and females of the high-dose group in the subchronic study; slight decreases in food consumption for females of all treatment groups in the subchronic study; and slight increases in relative liver weight for high-dose females in the 9-d study and high-dose males in the subchronic study, which is probably a compensatory hypertrophy for the metabolism of EHD. Thus, recurrent epicutaneous applications of undiluted EHD to the rat did not cause any local skin irritation or cumulative or organ-specific toxicity.

Accumulation of a commercial polychlorinated biphenyl mixture (Aroclor 1016) in adult rhesus monkeys and their nursing infants.

Female rhesus monkeys (24) were divided into 3 groups and fed diets calculated to contain 1.0, 0.25 or 0 parts per million (ppm) of a commercial mixture of polychlorinated biphenyls (PCBs), Aroclor 1016. The animals consumed a calculated total of 18.1 +/- 3.1, 4.5 +/- 0.6 and 0 mg Aroclor 1016/kg of body weight over the 87 +/- 9 week experimental period. All animals were bred, conceived and experienced uncomplicated pregnancies. The birth weights of the infants born to females receiving the 1.0 ppm PCB diets were significantly less than those of the control infants. There was a positive relationship between the levels of Aroclor 1016 in the tissues and the dose administered in the diets. Aroclor 1016 content of infant tissues was consistent with maternal adipose tissue PCB levels. The content of Aroclor 1016 in the milk fat of the animals more closely approximated that in the individual's adipose tissue than in the serum. At weaning, the mesenteric fat of the experimental infants contained concentrations of Aroclor 1016 which were 4-7 times that found in the mothers. Analyses of the tissues and fluids of the experimental animals demonstrated accumulation of PCB isomerides. The number of isomerides present and the ratio of those detected differed between adult and infants as well as between milk and serum. After weaning, the pattern of Aroclor 1016 isomerides present in the infants' adipose was similar to that observed at weaning although the concentrations had decreased.

Promoting effects of polychlorinated biphenyls (Aroclor 1254) and polychlorinated dibenzofuran-free Aroclor 1254 on diethylnitrosamine-induced tumorigenesis in the rat.

The hepatic tumor-promoting activity of a commercial polychlorinated biphenyl mixture, Aroclor 1254 (AR 1254), with and without its intrinsic polychlorinated dibenzofuran (PCDF) impurities, was investigated. Male Sprague-Dawley non-inbred albino rats were treated with 66 microgram diethylnitrosamine (DENA)/ml drinking water for 5 weeks and subsequently given a control diet or a diet supplemented (100 ppm for 18 wk) with either AR 1254 or AR 1254 from which the PCDF moieties were removed (AR 1254-PCDF). Of those animals receiving DENA alone, 16% exhibited hepatocellular carcinomas. Of those rats treated with DENA followed by administration of AR 1254 or AR 1254-PCDF, 64 or 84%, respectively, developed hepatocellular carcinomas. Thus promotion with either AR 1254 or AR 1254-PCDF significantly (P less than 0.05) increased the incidence of DENA-initiated hepatocellular carcinomas. Administration of AR 1254 or AR 1254-PCDF alone did not induce hepatic tumors. Therefore, PCDF impurities were not necessary for the promoting activity of AR 1254.

Absorption, tissue distribution and excretion of 14C ethylenethiourea by the rhesus monkey and rat.

Two female rhesus monkeys and four Sprague-Dawley rats were give 14C ethylenethiourea by gastric intubation and the rate of excretion was evaluated for 48 hours. The animals were subsequently sacrificed and the tissue distribution of 14C determined. The major route of 14C excretion was by way of the urine with 47 and 64% of the total radioactivity in the monkey urine and an average of 82% in the rat urine. The feces accounted for less than 1.5% of the radioactivity in both animal species. Tissue distribution accounted for 21 and 28% of the administered 14C in the monkey, while less than 1% was located in the rat tissues. The skin and musculature contained the largest amount of radioactivity in both species.

Urinary metabolites of 2, 5, 2', 5'-tetrachlorobiphenyl in the nonhuman primate.

The metabolism of 2, 5, 2', 5'-tetrachlorobiphenyl (TCB) in nonhuman primates was found to be different from that previously reported in lower species. Monohydroxy TCB (I), the only metabolite in the ether extracts of rat urine, is a minor metabolite in the urine of nonhuman primates. The two major metabolites identified in the urine were dihydroxy TCB (II) and trans-3,4-dihydro-3,4-dihydroxy TCB (III). A second minor metabolite was identified as hydroxy-3,4-dihydro-3,4-dihydroxy TCB (IV). None of the above mentioned metabolites have been reported in primates and only I and III have been identified in lower animals. It is concluded that a likely mechanism for metabolism of TCB in primates is through arene oxide intermediates. This observation is of particular importance in that these types of intermediates are known to alkylate cellular components causing carcinogenic, mutagenic, necrogenic and teratogenic effects.