Abstract  To elucidate the relationship between peroxisome proliferation by perfluorinated compounds and oxidative DNA damage, perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), perfluorobutyric acid (PFBA) and perfluorooctane (PFO) were administered to 6-week-old F-344 male rats. After a single intraperitoneal (i.p.) injection of PFOA, PFBA or PFO in corn oil at a dose of 100 mg/kg, significant increases of liver weight and 8-hydroxydeoxyguanosine (8-OH-dG) levels in liver DNA were observed in PFOA-treated rats. Oral administration of powdered diet containing 0.02% PFOA or 0.01% PFDA for 2 weeks resulted in significant increases of liver weight and 8-OH-dG levels in liver DNA in rats given both chemicals. On the other hand, no increase in 8-OH-dG levels in kidney DNA was found in either of the studies. Our results demonstrate that, as with other peroxisome proliferators (phthalic ester plasticizers and hypolipidemic drugs), PFOA and PFDA induced peroxisome proliferation also leads to organ specific oxidative DNA damage.

Abstract  The induction of peroxisome proliferation in rat liver was examined after administration of perfluoro-n-decanoic acid (PFDA, C10), perfluoro-n-octanoic acid (PFOA, C8), perfluoro-n-butyric acid (PFBA, C4), 1-H,1-H-pentadecafluoro-n-octanol (PFOL, C8) perfluorododecane (PFD, C12), and perfluorooctane (PFO, C8). The peroxisome proliferation in the liver was detected by the following methods; 1) measurement of liver weight, 2) assay of hepatic catalase activity, 3) analysis of 600 X g supernatant of liver homogenates by SDS-polyacrylamide gel electrophoresis to observe the induction of the bifunctional enoyl-CoA hydratase in peroxisomes (80K-protein) and 4) observation by electron microscopy. The oral administration of powdered chow containing 0.02%-PFOA and PFBA to male rats of the Sprague-Dawley strain for 2 weeks and the single intraperitoneal injection of corn oil mixed with PFDA, PFOA, and PFOL at the dose of 100 mg/kg induced peroxisome proliferation markedly. PFOL, which has two hydrogen atoms around the hydroxylated carbon, should be metabolized to PFOA, which is an active inducer. Perfluorinated paraffins, PFD and PFO, did not show any induction, indicating the importance of the carboxylic group in the molecule for the peroxisome proliferation. Although the participation of thyroid hormone cannot be excluded, PFOA appears to act directly on the liver.

Abstract  The effect of inhaled chloroform on embryonal and fetal development was evaluated in CF-1 mice. Bred mice were exposed to 0 or 100 ppm of chloroform for 7 hr/day from Days 1 through 7, 6 through 15, or 8 through 15 of gestation. Exposure to chloroform from Days 1 through 7 or 6 through 15 significantly impaired the ability of the female rats to maintain pregnancy but was not significantly teratogenic. In comparison, a significant increase in the incidence of cleft palate was observed among the offspring of mice inhaling chloroform from Days 8 through 15 of gestation, but no effect on the ability of the female rats to maintain pregnancy was discerned. Other signs of toxicity observed among the litters of mice exposed to chloroform included: decreased ossification of bones (all experimental groups), decreased incidence of resorptions (Days 1 through 7), and reduced fetal body measurements (Days 1 through 7 and 8 through 15).

Abstract  Mice, rats, and rabbits (five/sex/group) were exposed by inhalation to ethylbenzene (EB) vapors for 6 hr/day, 5 days/week for 4 weeks (20 exposures). Rats and mice received 0, 99, 382, or 782 ppm EB while rabbits received 0, 382, 782, or 1610 ppm. No changes were evident in mortality patterns, clinical chemistries, urinalyses, or treatment-related gross/microscopic (including ophthalmologic) lesions. Rats exhibited sporadic lacrimation and salivation, as well as significantly increased liver weights at 382 and 782 ppm, and small increases in leukocyte counts at 782 ppm. Males at this exposure level also showed marginal elevations in platelet counts. In mice, females showed statistically increased absolute and relative liver weights at 382 and 782 ppm, while males had statistically increased relative liver-to-brain weight ratios only at 782 ppm. Female rabbits at the high exposure level of 1610 ppm gained weight more slowly than controls (not statistically significant); males showed a similar transient downward trend after 1 week, but showed no differences from controls at study's end. A no observed adverse effect level (NOAEL) of 382 ppm appears appropriate for rats and mice with a lowest observed adverse effect level (LOAEL) of 782 ppm. A NOAEL of 782 ppm and LOAEL of 1610 ppm are appropriate for rabbits.

Abstract  The potential for neurotoxicological and immunotoxicological effects of ethylbenzene was studied in young adult Crl:CD(SD) rats following 90-day oral (neurotoxicity) or 28-day inhalation (immunotoxicity) exposures. In the neurotoxicity study, ethylbenzene was administered orally via gavage twice daily at 0, 25, 125, or 250 mg/kg per dose (total daily dosages of 0, 50, 250, or 500 mg/kg bwt/day [mg/kg bwt/day]) for 13 weeks and the functional observational battery (FOB), automated tests for motor activity and neuropathological examination were conducted. In the immunotoxicity study, animals were exposed by inhalation to 0, 25, 100, or 500 ppm ethylbenzene (approximately 26, 90, or 342 mg/kg bwt/day as calculated from physiologically based pharmacokinetic modeling). Immunotoxicity was evaluated in female rats using the splenic antibody-forming cell plaque-forming assay in sheep red blood cell sensitized animals. The no-observed-effect level for the oral gavage study was 50mg/kg bwt/day based on increased relative weights of the liver and kidneys in the male rats. The no-observed-adverse-effect level (NOAEL) for adult neurotoxicity was the highest dose tested 500 mg/kg bwt/day. The NOAEL for the immunotoxicity evaluation was the highest tested exposure concentration, 500 ppm (342 mg/kg bwt/day).

Abstract  Perfluorobutanesulfonate (PFBS) is a surfactant and degradation product of substances based on perfluorobutanesulfonyl fluoride. A two-generation reproductive rat study has been conducted with potassium PFBS (K(+)PFBS). Parental-generation (P) rats were dosed orally by gavage with 0, 30, 100, 300 and 1000mg K(+)PFBS/kg/day for 10 weeks prior to and through mating (males and females), as well as during gestation and lactation (females only). First generation (F1) pups were dosed similarly, beginning at weaning. Second generation (F2) pups were not directly dosed but potentially exposed to PFBS through placental transfer and nursing, and the study was terminated 3 weeks after their birth. Endpoints evaluated included body weight, food consumption, clinical signs, estrus cycling, sperm quality, pregnancy, natural delivery, litter outcomes, and developmental landmarks. The no-observable-adverse effect dose level (NOAEL) in the parental generations (P and F1) was 100mg/kg/day. In the 300 and 1000mg/kg/day dose group rats, there were (1) increased liver weight (absolute or relative) and corresponding increased incidence of adaptive hepatocellular hypertrophy (male only) and (2) increased incidence of minimal to mild microscopic findings in the medulla and papilla of the kidneys (male and female). There were no K(+)PFBS treatment-related effects on fertility or reproduction among the P or the F1 rats. There were no microscopic changes in male or female reproductive organs, and no biologically relevant effects on sperm parameters, mating, estrous cycles, pregnancy, and natural delivery in the P- or F1-generations. There were no K(+)PFBS treatment-related effects on survival of pups in the two-generation study. Litter size and average pup birth weight per litter were not statistically significantly different from controls in any dose group. In the F1-generation, terminal body weight was reduced in males at 1000mg/kg/day. Preputial separation was slightly delayed (approximately 2 days) at this dose, a finding consistent with the body weight reduction. Essentially no effects were observed in the F1 females. F2 pups had normal body weights. The reproductive NOAEL was >1000mg/kg/day in both generations.

Abstract  Perfluorononanoic acid (PFNA,C9),a synthetic perfluorinated chemical containing nine carbons, accumulates and is biomagnified through food webs. This compound has been detected in the serum of humans and wildlife and has the potential for reproductive interference. Few studies, however, have reported the effects of PFNA exposure on male reproduction. To determine this, male rats were orally dosed for 1, 3 and 5 mg/kg day PFNA or with vehicle for 14 days. In the present study, serum testosterone levels were decreased. while estradiol levels were increased dramatically in rats receiving 5 mg PFNA/kg day. Spermatogenic cells from rats that received 5 mg PFNA/kg day exhibited apoptotic features including crescent chromatin condensation and chromatin margination. Flow cytometric analysis and TUNEL assays revealed a dose-dependent increase of apoptotic cell numbers. In addition, expression of Fas and Bax mRNA levels were upregulated significantly, and Bcl-2 mRNA levels were downregulated markedly in the 3 and 5 mg/kg day groups. A dose-dependent increase in levels of active caspase-8 and no significant changes of active caspase-9 were observed. Our results indicate that PFNA exposure can lead to cell apoptosis in rat testis, and this apoptosis was probably associated with the Fas death receptor-dependent apoptotic pathway. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Abstract  Strain a/j mice were exposed by inhalation for 6 hours/day, 5 days/week, for six months to carbon disulfide, 1,2-dibromoethane, ethylene oxide, naphthalene, nitrogen dioxide, or vinyl chloride. Significant increases in pulmonary adenoma formation were observed following exposure to 300 ppm carbon disulfide; 20 and 50 ppm 1,2-dibromoethane; 70 and 200 ppm ethylene oxide; 10 ppm no 2; and 50, 200, and 500 ppm vinyl chloride compared with control animals. Exposure of mice to 30 ppm naphthalene did not elicit a significant adenoma response. The results provide further information for the validation of this in vivo model as a tool for predicting oncogenic potential following chemical exposure.

Abstract  Male rats were fed a diet that contained perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) at concentrations ranging from 0.0025-0.04% (w/w) and from 0.00125-0.01% (w/w), respectively, for 1 week. The hepatic responses of the rats to PFOA and PFDA were examined. Upon the administration of PFOA and PFDA, three peroxisome proliferator-responsive parameters, peroxisomal beta-oxidation, microsomal 1-acylglycerophosphocholine (1-acyl-GPC) acyltransferase and cytosolic long-chain acyl-CoA hydrolase, were induced in a dose-dependent manner. A multiple regression analysis of the three parameters revealed that the data from rats treated with PFOA and PFDA shared one common line, indicating a marked correlation among the inductions of the three parameters. The activities of glutathione (GSH) S-transferases towards 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzene (DCNB) were depressed by PFOA and PFDA. Significant inverse correlations were found between activities of GSH S-transferases and peroxisomal beta-oxidation. The administration of PFOA and PFDA significantly increased hepatic concentration of triacylglycerol. The perfluorocarboxylic acids at relatively high doses caused accumulation of cholesterol in liver. Electron microscopic studies showed that the administration of PFOA and PFDA caused an increase in cell size and proliferations of peroxisomes, and that the treatment of rats with PFDA at dietary concentration of 0.01% caused a marked increase in small lipid droplet in hepatocytes, indicative of hepatotoxic manifestations. The present results suggest that when PFOA and PFDA are administered at low levels, there are no differences between the properties of the perfluorocarboxylic acids as peroxisome proliferators, although the administration of PFDA at the doses exceeding a certain level becomes markedly toxic to hepatocytes.

Abstract  The weight of the mouse liver following feeding of ammonium perfluorooctanoate, ammonium perfluorononanoate, Telomer B ammonium sulfate, and WG-III was increased in a dose-dependent manner. Dietary levels of 3 ppm or greater ammonium perfluorooctanoate for either 14 or 21 days produced a significant elevation in liver weight both on an absolute and on an organ/body weight ratio basis. Similarly, ammonium perfluorononanoate produced significant increases at the lowest level tested, 3 ppm. Telomer B ammonium sulfate and WG-III also produced liver weight increases but at higher feeding levels. The striking increase in liver weight following relatively short-term exposures in mice makes this a useful screening test for comparing the liver-enlarging capacity of ammonium perfluorooctanoate and related fluorochemicals.

Abstract  This study was conducted to evaluate the potential adverse effects of ethylbenzene (EB) on reproductive capability from whole-body inhalation exposure of F0 and F1 parental animals.

Four groups of Crl:CD(SD)IGS BR rats (30/sex/group for F0 and 25/sex/group for F1) were exposed to 0, 25, 100, and 500 ppm EB for 6 hr/day for at least 70 consecutive days before mating. Inhalation exposure for the F0 and F1 females continued throughout mating, gestation through gestation day (GD) 20, and lactation days (LD) 5-21. On LD 1-4, females received EB in corn oil via oral gavage at dose levels of 26, 90, and 342 mg/kg/day (divided into three equal doses, approximately 2 hr apart), as calculated from a physiologically-based pharmacokinetic (PBPK) model to provide similar maternal blood area-under-concentration (AUC) as provided by inhalation. Pups were weaned on postnatal day (PND) 21 and exposure of the F1 generation started on PND 22. Estimates of internal exposure were determined by measuring EB concentrations in blood collected from F1 dams (4/group) and their culled pups 1 hr after the last gavage dose on PND 4. On PND 22, blood was collected from these same F1 dams and their weanlings for EB analysis 1 hr after a 6-hr inhalation exposure. The remainder of the F2 generation was not directly exposed.

EB exposure did not affect survival or clinical observations. Male rats in the 500 ppm group in both generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, ovarian follicle counts, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, pup weights, developmental landmarks, and postnatal survival were unaffected. No adverse exposure-related macroscopic pathology was noted at any level.

Increased liver weights were found in the animals exposed to 500 ppm. F1 maternal whole blood EB concentrations of 0.49, 3.51, or 18.28 mg/L were found 1 hr after administration of a composite oral dose of 26, 90, or 342 mg/kg/day, respectively, but no detectable EB was found in blood samples of their F2 PND 4 culled pups. F1 maternal mean whole blood EB levels 1 hr after a 6-hr inhalation exposure on postpartum day (PPD) 22 was 0.11 mg/L (25 ppm), 0.56 mg/L (100 ppm), and 11 mg/L (500 ppm). For the offspring exposed with their dams on PND 22, F2 pup blood EB concentrations ranged from 0.017-0.039 mg/L (25 ppm), 0.165-0.465 mg/L (100 ppm), and 8.82-15.74 mg/L (500 ppm). Because decreased weight gain in the 500 ppm males was transient and no histopathological changes were associated with the increased liver weights in the 500 ppm male and female groups, these changes were not considered adverse. Therefore, for parental systemic toxicity, 100 ppm was considered a NOEL and 500 ppm a NOAEL in this study. The 500 ppm exposure concentration was considered a NOAEL for F0 and F1 reproductive toxicity and offspring developmental endpoints.

Abstract  Perfluoroalkyl acid (PFAA)-induced apoptosis has been reported in many cell types. However, minimal information on its mode of action is available. This study explored the possible involvement of apoptotic signaling pathways in a nine-carbon-chain length PFAA-perfluorononanoic acid (PFNA)-induced splenocyte apoptosis. After a 14-day exposure to PFNA, rat spleens showed dose-dependent levels of apoptosis. The production of pro-inflammatory and anti-inflammatory cytokines was significantly increased and decreased, respectively. However, protein levels of tumor necrosis factor receptor 1 (TNFR1), fas-associated protein with death domain (FADD), caspase 8 and caspase 3, which are involved in inflammation-related and caspase-dependent apoptosis, were discordant. Peroxisome proliferator-activated receptors alpha (PPARalpha) and PPARgamma genes expression was up-regulated in rats treated with 3 or 5 mg/kg/day of PFNA, and the level of hydrogen peroxide (H2O2) increased concurrently in rats treated with the highest dose. Moreover, superoxide dismutase (SOD) activity and Bcl-2 protein levels were dramatically decreased in spleens after treatment with 3 and 5 mg/kg/day of PFNA. However, protein levels of Bax were unchanged. Apoptosis-inducing factor (AIF), an initiator of caspase-independent apoptosis, was significantly increased in all PFNA-dosed rats. Thus, oxidative stress and the activation of a caspase-independent apoptotic signaling pathway contributed to PFNA-induced apoptosis in rat splenocytes.

Abstract  Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα). In the current study, we used PPARα knockout (KO) and 129S1/SvlmJ wild-type (WT) mice to investigate the role of PPARα in mediating PFNA-induced in vivo effects. Pregnant KO and WT mice were dosed orally with water (vehicle control: 10 ml/kg), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GDs) 1-18 (day of sperm plug = GD 0). Maternal weight gain, implantation, litter size, and pup weight at birth were unaffected in either strain. PFNA exposure reduced the number of live pups at birth and survival of offspring to weaning in the 1.1 and 2 mg/kg groups in WT. Eye opening was delayed (mean delay 2.1 days) and pup weight at weaning was reduced in WT pups at 2 mg/kg. These developmental endpoints were not affected in the KO. Relative liver weight was increased in a dose-dependent manner in dams and pups of the WT strain at all dose levels but only slightly increased in the highest dose group in the KO strain. In summary, PFNA altered liver weight of dams and pups, pup survival, body weight, and development in the WT, while only inducing a slight increase in relative liver weight of dams and pups at 2 mg/kg in KO mice. These results suggest that PPARα is an essential mediator of PFNA-induced developmental toxicity in the mouse.

Abstract  The developmental toxicity of perfluorohexane sulfonate (PFHxS) is largely unknown despite widespread environmental contamination and presence in human serum, tissues and milk.To thoroughly investigate PFHxS toxicity in developing rats and to mimic a realistic human exposure situation, we examined a low dose close to human relevant PFHxS exposure, and combined the dose-response studies of PFHxS with a fixed dose of twelve environmentally relevant endocrine disrupting chemicals (EDmix).Two reproductive toxicity studies in time-mated Wistar rats exposed throughout gestation and lactation were performed. Study 1 included control, two doses of PFHxS and two doses of PFHxS+EDmix (n = 5-7). Study 2 included control, 0.05, 5 or 25 mg/kg body weight/day PFHxS, EDmix-only, 0.05, 5 or 25 mg PFHxS/kg plus EDmix (n = 13-20).PFHxS caused no overt toxicity in dams and offspring but decreased male pup birth weight and slightly increased liver weights at high doses and in combination with the EDmix. A marked effect on T4 levels was seen in both dams and offspring, with significant reductions from 5 mg/kg/day. The EDmix caused anti-androgenic effects in male offspring, manifested as slight decreases in anogenital distance, increased nipple retention and reductions of the weight of epididymides, ventral prostrate and vesicular seminalis.PFHxS can induce developmental toxicity and in addition results of the co-exposure studies indicated that PFHxS and the EDmix potentiate the effect of each other on various endpoints, despite their different modes of action. Hence, risk assessment may underestimate toxicity when mixture toxicity and background exposures are not taken into account.

Abstract  Adverse intrauterine environments have been associated with increased risk of later cardiovascular disease and hypertension. In an animal model using diverse developmental toxicants, we measured blood pressure (BP), renal nephron endowment, renal glucocorticoid receptor (GR) gene expression, and serum aldosterone in offspring of pregnant Sprague-Dawley rats exposed to dexamethasone (Dex), perfluorooctane sulfonate (PFOS), atrazine, perfluorononanoic acid (PFNA), arsenic or nicotine. BP was assessed by tail cuff photoplethysmography, nephron endowment by confocal microscopy, and renal GR mRNA by qPCR. BP was also measured by telemetry, and corticosterone (CORT) was measured in resting or restrained Dex and atrazine offspring. Treated dams gained less weight during treatment in all groups except arsenic. There were chemical- and sex-specific effects on birth weight, but offspring body weights were similar by weaning. BP was higher in Dex, PFOS, atrazine and PFNA male offspring by 7-10 weeks. Female offspring exhibited elevated BP at 10 weeks for PFNA and arsenic, and at 37 weeks for Dex, PFOS and atrazine. Dex, PFOS and atrazine offspring still exhibited elevated BP at 52-65 weeks of age; others did not. Elevated BP was associated with lower nephron counts. Dex, PFOS and atrazine offspring had elevated renal GR gene expression. Elevations in BP were also observed in Dex and atrazine offspring by radiotelemetry. Atrazine offspring exhibited enhanced CORT response to restraint. Elevated offspring BP was induced by maternal exposure to toxicants. Since all treatments affected maternal gestational weight gain, maternal stress may be a common underlying factor in these observations.

Abstract  Perfluorodecanoic acid (PFDA) is a 10-carbon straight-chain fatty acid. Its toxicity in rats has been reported to resemble that produced by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Mice which are "responsive" to TCDD toxicity carry the Ahb allele, while mice homozygous for the Ahd gene are less sensitive to TCDD toxicity. To characterize the toxicity of PFDA and determine if it is under the control of the Ah locus, female responsive C57BL/6N (Ahb/b) mice and congenic C57BL/6J mice, differing only at the Ah locus (responsive, Ahb/b; heterozygous responsive, Ahb/d and "nonresponsive," Ahd/d), were administered a single oral dose of PFDA, at levels from 0 to 320 mg/kg body weight, observed daily for overt signs of toxicity, and weighed three times weekly. In the wild-type congenic C57BL/6J (Ahb/b) subline, mice were killed at 2, 7, 14, and 30 days following exposure. All other mice were killed on Day 30. Serum was taken from the C57BL/6N mice for analysis of thyroid hormone levels. Selected organs from all mice were weighed and fixed for histopathological examination. Dose-related mortality was observed as early as 5 days postexposure and time-to-death was inversely related to dose. Dramatic decreases in body weight occurred shortly following treatment in all strains. Serum triiodothyronine (T3) and thyroxine (T4) levels increased with increasing dose. There was a marked increase (p less than 0.05) in absolute and relative liver weights and a significant decrease in thymus weights. Hepatocellular hypertrophy was observed in all treated mice other than controls. A marked increase in hepatocyte peroxisomes was observed in all treatment groups. Thus, in contrast to TCDD, the acute toxicity of PFDA in the female C57BL/6 mouse does not vary with the Ah allele and is distinct from that reported for TCDD.

Abstract  The reproductive toxicity and teratogenic potential of 19 industrial chemicals have been investigated during the past 3 a. Preliminary studies utilizing intraperitoneal treatments of rats on days 1-15 of gestation have been conducted on the following ten chemicals: allyl chloride, bisphenol A, copper naphthenate, ethylene dibromide, hexachlorobutadiene, 2-mercaptobenzothiazole, methyl styrene, naphthalene, 2-nitropropane, and 1,2,3-trichloropropane. Studies utilizing inhalation exposure of rats and rabbits on days 1-19 and 1-24, respectively, of gestation have been conducted on the following nine chemicals: butylene oxide, carbon disulfide, 2-ethoxyethanol, ethyl benzene, methyl bromide, nitrous oxide, styrene oxide, tetrachloroethylene, and trichloroethylene. In the preliminary studies, evidence of teratogenic potential was seen with allyl chloride and bisphenol A, and fetal toxicity was found in the absence of maternal toxicity with methyl styrene and 2-nitropropane. In the inhalation studies, 2-ethoxyethanol was strongly embryotoxic at the higher exposure levels employed and was teratogenic at the lower concentration.

Abstract  Random bred CD-1 mice were used to evaluate the acute oral toxicity and subchronic toxicity of naphthalene administered in corn oil. The acute oral LD50 of naphthalene was 533 and 710 mg/kg in male and female mice, respectively. Subchronic toxicity was evaluated with 14- and 90-day daily oral gavage studies. Doses utilized in the 14-day study were 27, 53, and 267 mg/kg, with the latter representing one-half of the male LD50. Both males and females demonstrated a 5-10% mortality and depressed body weight at the high dose only. Males had decreased thymus weights, and females had decreased spleen and increased lung weights at the high dose only. Other organ weights were unaffected at any dosage level. Serum enzyme and electrolyte levels were not altered in a dose-related manner. To assess the potential immunotoxicity of naphthalene the following screen was utilized: humoral immune response, response to mitogens, delayed hypersensitivity response, popliteal lymph node response, bone marrow stem cell number, and DNA synthesis. No evidence of immunotoxicity was demonstrated. The 90-day study employed daily oral doses of 5.3, 53, and 133 mg/kg. There was no treatment-related mortality in either sex, nor was body weight affected. Organ weights were not affected in males, and females showed reduced spleen weights only at the high dose. Serum enzyme and electrolyte levels, as well as the immunotoxicity screen, indicated that naphthalene doses up to one-fourth the LD50 for 90 days failed to elicit consistent statistically significant and biologically relevant compound-related effects. A screen of the effects of the 90-day naphthalene treatment on various aspects of the hepatic drug metabolizing system indicated no alterations, with the exception of a specific dose-related inhibition of aryl hydrocarbon hydroxylase activity in both male and female mice.

Abstract  This study evaluated the effects of inhalation of subanesthetic concentrations of chloroform on rat embryonal and fetal development. Pregnant Sprague-Dawley rats were exposed to 30, 100 or 300 ppm chloroform for 7hr/day on days 6 through 15 of gestation. Exposure to chloroform caused an apparent decrease in the conception rate and a high incidence of fetal resorption (300 ppm), retarded fetal development (30, 100, 300 ppm), decreased fetal body measurements (30, 300 ppm) and a low incidence of acaudate fetuses with imperforate anus (100 ppm). Chloroform was not highly teratogenic but was highly embryotoxic. The results of this study disclosed no relationship between maternal toxicity and embryo or fetotoxicity as the result of exposure to chloroform by inhalation.

Abstract  BACKGROUND: Perfluoroalkyl substances (PFAS) are suggested to affect human fecundity through longer time to pregnancy (TTP). We studied the relationship between four abundant PFAS and TTP in pregnant women from Greenland, Poland and Ukraine representing varying PFAS exposures and pregnancy planning behaviors.

METHODS: We measured serum levels of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) in 938 women from Greenland (448 women), Poland (203 women) and Ukraine (287 women). PFAS exposure was assessed on a continuous logarithm transformed scale and in country-specific tertiles. We used Cox discrete-time models and logistic regression to estimate fecundability ratios (FRs) and infertility (TTP >13 months) odds ratios (ORs), respectively, and 95% confidence intervals (CI) according to PFAS levels. Adjusted analyses of the association between PFAS and TTP were done for each study population and in a pooled sample.

RESULTS: Higher PFNA levels were associated with longer TTP in the pooled sample (log-scale FR = 0.80; 95% CI 0.69-0.94) and specifically in women from Greenland (log-scale FR = 0.72; 95% CI 0.58-0.89). ORs for infertility were also increased in the pooled sample (log-scale OR = 1.53; 95% CI 1.08-2.15) and in women from Greenland (log-scale OR = 1.97; 95% CI 1.22-3.19). However, in a sensitivity analysis of primiparous women these associations could not be replicated. Associations with PFNA were weaker for women from Poland and Ukraine. PFOS, PFOA and PFHxS were not consistently associated with TTP.

CONCLUSIONS: Findings do not provide consistent evidence that environmental exposure to PFAS is impairing female fecundity by delaying time taken to conceive.

Abstract  Perfluoroalkyl chemicals (PFASs) are a class of highly stable man-made compounds, and their toxicological impacts are currently of worldwide concern. Administration of perfluorononanoic acid (PFNA), a perfluorocarboxylic acid (PFCA) with a nine carbon backbone, resulted in dose-dependent hepatomegaly in mice (0, 0.2, 1, and 5 mg/kg body weight, once a day for 14 days) and an increase in hepatic triglycerides (TG) and total cholesterol (TCHO) in the median dose group as well as serum transaminases in the high dose group. Using isobaric tags for relative and absolute quantitation (iTRAQ), we identified 108 (80 up-regulated, 28 down-regulated) and 342 hepatic proteins (179 up-regulated, 163 down-regulated) that exhibited statistically significant changes (at least a 1.2-fold alteration and P < 0.05) in the 1 and 5 mg/kg/d PFNA treatment groups, respectively. Sixty-six proteins (54 up-regulated, 12 down-regulated) significantly changed in both of the two treatment groups. Among these 54 up-regulated proteins, most were proteins related to the lipid metabolism process (31 proteins). The mRNA analysis results further suggested that PFNA exposure not only resulted in a fatty acid oxidation effect but also activated mouse liver genes involved in fatty acid and cholesterol synthesis. Additionally, three (2 down-regulated, 1 up-regulated) and 30 (14 down-regulated, 16 up-regulated) microRNAs (miRNAs) exhibited at least a 2-fold alteration (P < 0.05) in the 1 and 5 mg/kg/d PFNA treatment groups, respectively, Three miRNAs (up-regulated: miR-34a; down-regulated: miR-362-3p and miR-338-3p) significantly changed in both of the two treatment groups. The repression effect of miR-34a on fucosyltransferase 8 (Fut8) and lactate dehydrogenase (Ldha) was confirmed by luciferase activity assay and Western blot analysis. The results implied that PFNA exerted a hepatic effect, at least partially, by miRNAs mediated post-translational protein repression.

Abstract  Naphthalene (CAS No. 91-20-3) administered by inhalation at concentrations of 10, 30, or 60 ppm for 6 hours per day, 5 days per week for 105 weeks caused nonneoplastic and neoplastic effects in nasal respiratory and olfactory regions of male and female F344/N rats. Non-neoplastic nasal effects were characterized by an increase in the incidence and severity of a complex group of lesions, including atypical hyperplasia, atrophy, chronic inflammation, and hyaline degeneration of olfactory epithelium; hyperplasia, squamous metaplasia, hyaline degeneration, and goblet cell hyperplasia of the respiratory epithelium; and hyperplasia and squamous metaplasia of mucosal glands. Neoplastic effects were characterized by the induction of two types of rare primary nasal tumors, olfactory neuroblastomas and respiratory epithelial adenomas. The incidences of olfactory neuroblastomas in males at 0 ppm, 10 ppm, 30 ppm, and 60 ppm were, respectively, 0%, 0%, 8%, and 6%, whereas in females they were 0%, 4%, 6%, and 24%. The incidences of respiratory epithelial adenomas in males at 0 ppm, 10 ppm, 30 ppm, and 60 ppm were, respectively, 0%, 12%, 17%, and 31% and in females 0%, 0%, 8%, and 4%. The olfactory neuroblastomas and respiratory epithelial adenomas were considered carcinogenic effects related to naphthalene exposure based on their relatively high incidence in exposed rats, their absence in concurrent control rats and NTP historical controls, and their rare spontaneous occurrence in rats of any strain.