Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis.

A comprehensive weight-of-the-evidence evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D) was conducted for potential interactions with the estrogen, androgen and thyroid pathways and with steroidogenesis. This assessment was based on an extensive database of high quality in vitro, in vivo ecotoxicological and in vivo mammalian toxicological studies. Epidemiological studies were also considered. Toxicokinetic data provided the basis for determining rational cutoffs above which exposures were considered irrelevant to humans based on exceeding thresholds for saturation of renal clearance (TSRC); extensive human exposure and biomonitoring data support that these boundaries far exceed human exposures and provide ample margins of exposure. 2,4-D showed no evidence of interacting with the estrogen or androgen pathways. 2,4-D interacts with the thyroid axis in rats through displacement of thyroxine from plasma binding sites only at high doses exceeding the TSRC in mammals. 2,4-D effects on steroidogenesis parameters are likely related to high-dose specific systemic toxicity at doses exceeding the TSRC and are not likely to be endocrine mediated. No studies, including high quality studies in the published literature, predict significant endocrine-related toxicity or functional decrements in any species at environmentally relevant concentrations, or, in mammals, at doses below the TSRC that are relevant for human hazard and risk assessment. Overall, there is no basis for concern regarding potential interactions of 2,4-D with endocrine pathways or axes (estrogen, androgen, steroidogenesis or thyroid), and thus 2,4-D is unlikely to pose a threat from endocrine disruption to wildlife or humans under conditions of real-world exposures.

An assessment of neurotoxicity of aroclors 1016, 1242, 1254, and 1260 administered in diet to Sprague-Dawley rats for one year.

As part of a comparative chronic toxicity/oncogenicity study of different Aroclors (1016, 1242, 1254, and 1260), neurotoxicity was assessed in male and female Sprague-Dawley rats using functional observational battery (FOB) and motor activity tests, and histopathologic evaluation of selected nervous system tissues. Doses varied by Aroclor and ranged from 25 to 200 ppm in the diet. Animals were evaluated prior to initiation of dosing and at 13, 26, 39, and 52 weeks of exposure. Clinical signs, body weights, and feed consumption were evaluated weekly. Data analysis of FOB and motor activity results revealed several instances where Aroclor-treated groups were different from control. However, these were considered incidental, as they lacked any consistent dose- or time-related pattern that would suggest Aroclor-induced neurotoxicity. The nonremarkable findings during each of the four assessments were supported by the absence of any treatment-related clinical signs or mortality. Decreased body weight gain was evident in the male 100 ppm Aroclor 1254 dose group and in all female Aroclor 1254 dose groups late in the study (when a linear relationship was assumed between body weight and time), correlating with decreased feed consumption. Although a variety of incidental, spontaneous, degenerative changes were found in nervous tissue evaluated histopathologically, these changes were seen with similar incidence and severity in treated and control groups. No lesions were found that could be attributed to Aroclor-related neurotoxicity. In summary, 52 weeks of exposure to Aroclors 1016, 1242, 1254, or 1260 mixed in the diet did not yield any functional or morphologic changes indicative of PCB-induced neurotoxicity.

A review of the developmental and reproductive toxicity of styrene.

The reproductive and developmental toxicity of styrene has been studied in animals and humans. The animal studies on styrene have diverse study designs and conclusions. Developmental or reproductive toxicity studies have been conducted in rats, mice, rabbits, and hamsters. In most cases, high doses are required to elicit effects, and the effects are not unique to reproduction or development. In a number of the reports, either the experimental designs are limited or the descriptions of the designs and the endpoints measured are insufficient to draw conclusions about the toxicity of styrene. The more complete and better-reported studies show that styrene does not cause developmental toxicity at dose levels that are not maternally toxic. Some neurochemical or neurobehavioral effects have been reported at high exposures. Styrene does not affect fertility or reproductive function. Considerable animal toxicity data on styrene support the conclusion that styrene is neither an endocrine-active substance nor an endocrine disrupter. Human studies often suffer from either inadequate exposure data or exposure to a wide variety of materials, so that attribution of effects to styrene exposure is impossible. Furthermore, investigators often have failed to account for other exposures in the workplace or for other potentially confounding factors in their studies. Menstrual cycle irregularities and congenital abnormalities were initially reported; however, the better and more recent reports do not show that styrene causes developmental or reproductive effects in humans. Human studies also support the conclusion that styrene is not an endocrine disrupter. Although some study authors have concluded that styrene is either a human or an animal reproductive or developmental toxicant, careful review demonstrates that such conclusions are not justified.

Comparative carcinogenicity in Sprague-Dawley rats of the polychlorinated biphenyl mixtures Aroclors 1016, 1242, 1254, and 1260.

A comprehensive chronic toxicity and carcinogenicity study was conducted on a series of Aroclors (1016, 1242, 1254, and 1260). Each Aroclor was assessed at multiple dietary concentrations, ranging from 25 to 200 ppm, for 24 months in male and female Sprague-Dawley rats. Liver toxicity was indicated by elevated serum enzyme activity (AST, ALT, and GGT), elevated serum cholesterol concentration, decreases in hematologic parameters (RBC, Hb, and Hct), hepatocellular hypertrophy, an increased incidence of altered hepatocellular foci, and an increased incidence of hepatocellular neoplasms (primarily adenomas). Liver toxicity was distinctly more severe in females than in males. The incidence of hepatocellular neoplasms was highly sex-dependent (females >> males), differed between Aroclor mixtures and, for females, increased with dose and followed the general incidence pattern of Aroclor 1254 > Aroclor 1260 approximately Aroclor 1242 > Aroclor 1016. A significant response (p < 0.05) in males was seen only for the high dose of Aroclor 1260. A small increase in the incidence of thyroid gland follicular cell adenomas was noted in males for Aroclors 1242, 1254, and 1260, with the incidence being uniform across dose groups and Aroclor mixtures. For females, increased survival relative to controls was observed for all Aroclor treatment groups. A significantly decreased trend in the incidence of mammary gland neoplasms compared to control was also noted for females receiving Aroclors 1242, 1254, and 1260.

Survey and assessment of mammalian estrogen biological assays for hazard characterization.

With the growing awareness and concern regarding estrogens in the environment, the selection of reliable and appropriate methods for their detection and characterization has taken on considerable importance. The relevant literature covering the period from 1920 to 1996 was surveyed to identify methods that have been used to assay estrogens in mammalian systems. The estrogen biological assays identified were grouped into four categories: (1) reproductive tract response; (2) non-reproductive-tract target tissue response; (3) estrogen receptor binding; and (4) estrogen receptor-dependent transcriptional expression. The biological assays were summarized and their advantages and disadvantages discussed. A possible testing scheme also was provided to characterize estrogens, anti-estrogens, and pro-estrogens (chemicals metabolically converted to estrogens)..