Range of the perfluorooctanoate (PFOA) safe dose for human health: An international collaboration.

Many government agencies and expert groups have estimated a dose-rate of perfluorooctanoate (PFOA) that would protect human health. Most of these evaluations are based on the same studies (whether of humans, laboratory animals, or both), and all note various uncertainties in our existing knowledge. Nonetheless, the values of these various, estimated, safe-doses vary widely, with some being more than 100,000 fold different. This sort of discrepancy invites scrutiny and explanation. Otherwise what is the lay public to make of this disparity? The Steering Committee of the Alliance for Risk Assessment (2022) called for scientists interested in attempting to understand and narrow these disparities. An advisory committee of nine scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three technical teams (for a total of 24 scientists from 8 countries). The teams reviewed relevant information and independently developed ranges for estimated PFOA safe doses. All three teams determined that the available epidemiologic information could not form a reliable basis for a PFOA safe dose-assessment in the absence of mechanistic data that are relevant for humans at serum concentrations seen in the general population. Based instead on dose-response data from five studies of PFOA-exposed laboratory animals, we estimated that PFOA dose-rates 10-70 ng/kg-day are protective of human health.

Hydroquinone PBPK model refinement and application to dermal exposure.

A physiologically based pharmacokinetic (PBPK) model for hydroquinone (HQ) was refined to include an expanded description of HQ-glucuronide metabolites and a description of dermal exposures to support route-to-route and cross-species extrapolation. Total urinary excretion of metabolites from in vivo rat dermal exposures was used to estimate a percutaneous permeability coefficient (K(p); 3.6×10(-5) cm/h). The human in vivo K(p) was estimated to be 1.62×10(-4) cm/h, based on in vitro skin permeability data in rats and humans and rat in vivo values. The projected total multi-substituted glutathione (which was used as an internal dose surrogate for the toxic glutathione metabolites) was modeled following an exposure scenario based on submersion of both hands in a 5% aqueous solution of HQ (similar to black and white photographic developing solution) for 2 h, a worst-case exposure scenario. Total multi-substituted glutathione following this human dermal exposure scenario was several orders of magnitude lower than the internal total glutathione conjugates in rats following an oral exposure to the rat NOEL of 20 mg/kg. Thus, under more realistic human dermal exposure conditions, it is unlikely that toxic glutathione conjugates (primarily the di- and, to a lesser degree, the tri-glutathione conjugate) will reach significant levels in target tissues.

Carcinogenicity and chronic toxicity of di-2-ethylhexyl terephthalate (DEHT) following a 2-year dietary exposure in Fischer 344 rats.

The carcinogenicity and chronic toxicity potential of di-2-ethylhexyl terephthalate (DEHT) was assessed in F-344 rats (50/sex/dose) by dietary exposure for 104 weeks. Exposure levels of 0, 1500, 6000 or 12,000 ppm resulted in average daily doses of 79, 324 and 666 mg/kg/day for males and 102, 418 and 901 mg/kg/day for females. Animals were observed daily for clinical signs and detailed physical examinations were performed weekly. Body weight and food consumption were measured at scheduled intervals. During weeks 103-104, urine and blood samples were collected and analyzed. Eyes were examined during week 104 using a binocular indirect ophthalmoscope. At necropsy, organs were weighed and examined macroscopically and microscopically. No histological effects were noted in any organ at any dose and there was no increase in the incidence of any tumor types. Toxic responses were confined to lower weight gains and food conversion efficiency in males and females ingesting 6000 or 12,000 ppm. The severity of a normal geriatric degenerative retinal change was exacerbated in females exposed to 6000 or 12,000 ppm and in males exposed to 12,000 ppm. Therefore, the no-observed effect level (NOEL) for tumorigenicity was 12,000 ppm and the NOEL for chronic toxicity was 1500 ppm.

Developmental toxicity and uterotrophic studies with di-2-ethylhexyl terephthalate.

BACKGROUND: These studies were conducted to evaluate the potential adverse effects of di-2-ethylhexyl terephthalate (DEHT) exposure on in utero development in mice and rats. In addition, a uterotrophic assay for estrogenic activity was conducted in sexually immature rats. METHODS: In the developmental toxicity studies, diet containing DEHT was fed to four groups of mated female Crl:CD(SD)IGS BR rats (25/group) from gestation day (GD) 0-20 or Crl:CD1(ICR) mice (25/group) from GD 0-18. Concentrations within the feed were 0, 0.3, 0.6, and 1.0% for the rats and 0, 0.1, 0.3, and 0.7% for the mice. Laparohysterectomies were carried out on the last day of exposure and the numbers of fetuses, early and late resorptions, total implantations, and corpora lutea were recorded. The fetuses were weighed, sexed, and examined for external, visceral and skeletal malformations, and developmental variations. The dose rate from dietary DEHT exposure was 0, 226, 458, and 747 mg/kg/day in the rats and 197, 592, and 1382 mg/kg/day in the mice for the control, low, mid, and high-exposure groups, respectively. RESULTS: DEHT exposure did not affect clinical observations. A slight reduction in body weight gain was noted in the high-dose level rat group; the remaining groups were unaffected. At necropsy, increased liver weights were noted in the high-dose rat group and the mid- and high-dose mouse groups. Mean numbers of implantation sites and viable fetuses, mean fetal weights, and mean litter proportions of preimplantation loss, early resorptions, late resorptions, and fetal sex ratios were unaffected by DEHT exposures. No test article-related malformations or variations were observed at any concentration level in the rat and mouse developmental toxicity studies. In the uterotrophic assay for estrogenic activity, sexually immature female rats received oral gavage doses 20, 200, or 2000 mg DEHT/kg bw/day from postnatal day (PND) 19-21. A slight reduction in rate of body weight gain was noted on the first day of dosing in the high dose group, but no other indications of toxicity were evident. DEHT exposure did not affect wet or blotted uterine weight parameters in any of these dose groups. The NOEL for developmental toxicity in rats was 747 mg/kg/day and 1382 mg/kg/day in mice. The NOEL for estrogenic activity was 2000 mg/kg/day. The NOEL for maternal toxicity was 458 mg/kg/day in rats and 197 mg/kg/day in mice. CONCLUSIONS: The lack of adverse developmental effects with DEHT exposure are in contrast to the adverse developmental effects noted after di-2-ethylhexyl phthalate (DEHP) exposure. The difference between the effects noted with the ortho-constituent (DEHP) and the lack of effects reported with the para-constituent (DEHT) is due most likely to differences in metabolism and the formation of the stable monoester, mono-2-ethylhexyl phthalate (MEHP) from the DEHP moiety.

Two-generation reproduction study of di-2-ethylhexyl terephthalate in Crl:CD rats.

BACKGROUND: This study was conducted to evaluate the potential adverse effects of di-2-ethylhexyl terephthalate (DEHT) on reproductive capability from exposure of F(0) and F(1) parental animals. METHODS: Four groups of male and female Crl:CD (SD)IGS BR rats (30/gender/group) were exposed to 0, 0.3%, 0.6%, and 1.0% DEHT in the feed for at least 70 consecutive days before mating for the F(0) and F(1) generations. Exposure for the F(0) and F(1) males continued throughout the mating period until euthanasia. Exposure for the F(0) and F(1) females continued throughout mating, gestation, and lactation. The F(1) and F(2) pups were weaned on postnatal day (PND) 21. Assessments included gonadal function, estrous cyclicity, mating behavior, conception rate, gestation, parturition, lactation, and weaning in the F(0) and F(1) generations, and F(1) generation offspring growth and development. RESULTS: DEHT exposure did not affect clinical observations. However, lethality was observed in F(0) and F(1) dams consuming the 1.0% diet during the post-weaning period. No treatment-related mortality occurred in any of the male groups exposed to DEHT or in the female groups exposed to 0.3% or 0.6% DEHT. Male rats consuming the 1.0% diet in both parental generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either the F(0) or F(1) generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, developmental landmarks, and postnatal survival were similar in all exposure groups. Additionally, ovarian follicle counts for the F(1) females in the high-exposure group were similar to the control values. No adverse exposure-related macroscopic pathology was noted at any exposure level in the F(0) and F(1) generations. CONCLUSIONS: Increases in liver weights were found in the male and female animals exposed to 0.6% or 1.0% DEHT in the diet. Because there were no accompanying histopathologic changes, this effect was not considered adverse. Significant decreases in feed consumption in the female animals from the groups consuming 1.0% DEHT in the diet during lactation accompanied reduced postnatal pup body weights and rate of weight gain. Reductions in pup body weights later in lactation may also have been due to direct consumption of the treated feed by the pups or taste aversion to the same. Reduced relative spleen weight was found in male weanling pups from the 1.0% group in both generations and reduced relative spleen and thymus weights were found in female pups from the 1.0% group in the F(2) generation at necropsy on PND 21. Therefore, for parental and pup systemic toxicity, 0.3% DEHT in the diet (182 mg/kg/day) was considered no-observed-effect level (NOEL). The 1.0% DEHT (614 mg/kg/day) in the diet exposure concentration was considered a NOEL for F(0) and F(1) reproductive toxicity endpoints.

Subchronic toxicity of ethylene glycol in Wistar and F-344 rats related to metabolism and clearance of metabolites.

Ethylene glycol (CAS RN 107-21-1) can cause kidney toxicity via the formation of calcium oxalate crystals in a variety of species, including humans. Numerous repeated dose studies conducted in rats have indicated that male rats are more susceptible than female rats. Furthermore, subchronic and chronic studies using different dietary exposure regimens have indicated that male Wistar rats may be more sensitive to renal toxicity than male Fischer-344 (F-344) rats. This study was conducted to compare the toxicity of ethylene glycol in the two strains of rats under identical exposure conditions and to evaluate the potential contribution of toxicokinetic differences to strain sensitivity. Ethylene glycol was mixed in the diet at concentrations to deliver constant target dosage levels of 0, 50, 150, 500, or 1000 mg/kg/day for 16 weeks to groups of 10 male Wistar and 10 male F-344 rats based on weekly group mean body weights and feed consumption. Kidneys were examined histologically for calcium oxalate crystals and pathology. Samples of blood, urine, and kidneys from satellite animals exposed to 0, 150, 500, or 1000 mg/kg/day for 1 or 16 weeks were analyzed for ethylene glycol, glycolic acid, and oxalic acid. Treatment of Wistar rats at 1000 mg/kg/day resulted in the death of two rats; in addition, at 500 and 1000 mg/kg/day, group mean body weights were decreased compared to control throughout the 16 weeks. In F-344 rats exposed at 1000 mg/kg/day and in Wistar rats receiving 500 and 1000 mg/kg/day, there were lower urine specific gravities, higher urine volumes, and increased absolute and relative kidney weights. In both strains of rats treated at 500 and 1000 mg/kg/day, some or all treated animals had increased calcium oxalate crystals in the kidney tubules and crystal nephropathy. The effect was more severe in Wistar rats than in F-344 rats. Accumulation of oxalic acid in the kidneys of both strains of rats was consistent with the dose-dependent and strain-dependent toxicity. As the nephrotoxicity progressed over the 16 weeks, the clearance of ethylene glycol and its metabolites decreased, exacerbating the toxicity. Benchmark dose analysis indicated a BMDL05 for kidney toxicity in Wistar rats of 71.5 mg/kg/day; nearly fourfold lower than in F-344 rats (285 mg/kg/day). This study confirms that the Wistar rat is more sensitive to ethylene glycol-induced renal toxicity than the F-344 rat and indicates that metabolism or clearance plays a role in the strain differences.