Sociability—the tendency to seek social interaction–propels the development of social cognition and social skills, but is disrupted in autism spectrum disorders (ASD). BALB/cJ and C57BL/6J inbred mouse strains are useful models of low and high levels of juvenile sociability, respectively, but the neurobiological and developmental factors that account for the strains’ contrasting sociability levels are largely unknown. We hypothesized that BALB/cJ mice would show increasing sociability with age but that C57BL/6J mice would show high sociability throughout development. We also hypothesized that littermates would resemble one another in sociability more than non-littermates. Finally, we hypothesized that low sociability would be associated with low corpus callosum size and increased brain size in BALB/cJ mice. Separate cohorts of C57BL/6J and BALB/cJ mice were tested for sociability at 19-, 23-, 31-, 42-, or 70-days-of-age, and brain weights and mid-sagittal corpus callosum area were measured. BALB/cJ sociability increased with age, and a strain by age interaction in sociability between 31 and 42 days of age suggested strong effects of puberty on sociability development. Sociability scores clustered according to litter membership in both strains, and perinatal litter size and sex ratio were identified as factors that contributed to this clustering in C57BL/6J, but not BALB/cJ, litters. There was no association between corpus callosum size and sociability, but smaller brains were associated with lower sociability in BALB/cJ mice. The associations reported here will provide directions for future mechanistic studies of sociability development.

Weight of evidence (WoE) approaches are recommended for interpreting various toxicological data, but few systematic and transparent procedures exist. A hypothesis-based WoE framework was recently published focusing on the U.S. EPA's Tier 1 Endocrine Screening Battery (ESB) as an example. The framework recommends weighting each experimental endpoint according to its relevance for deciding eight hypotheses addressed by the ESB. Here we present detailed rationale for weighting the ESB endpoints according to three rank ordered categories and an interpretive process for using the rankings to reach WoE determinations. Rank 1 was assigned to in vivo endpoints that characterize the fundamental physiological actions for androgen, estrogen, and thyroid activities. Rank 1 endpoints are specific and sensitive for the hypothesis, interpretable without ancillary data, and rarely confounded by artifacts or nonspecific activity. Rank 2 endpoints are specific and interpretable for the hypothesis but less informative than Rank 1, often due to oversensitivity, inclusion of narrowly context-dependent components of the hormonal system (e.g., in vitro endpoints), or confounding by nonspecific activity. Rank 3 endpoints are relevant for the hypothesis but only corroborative of Ranks 1 and 2 endpoints. Rank 3 includes many apical in vivo endpoints that can be affected by systemic toxicity and nonhormonal activity. Although these relevance weight rankings (W REL ) necessarily involve professional judgment, their a priori derivation enhances transparency and renders WoE determinations amenable to methodological scrutiny according to basic scientific premises, characteristics that cannot be assured by processes in which the rationale for decisions is provided post hoc.

A framework has been evolving for evaluation of mode of action (MOA) of rodent toxicity and carcinogenicity findings and their relevance to humans. Folpet produces duodenal glandular tumors in mice, but is not carcinogenic in rats. A wealth of information is available regarding folpet's mode of action, providing an excellent example of how this tumor can be evaluated using this framework. Folpet reacts with thiol groups, and is rapidly hydrolyzed at pH 7. Both reactions produce thiophosgene that reacts with thiols and other functional groups. Folpet is not genotoxic in vivo. At sufficiently high, prolonged dietary doses, folpet irritates the mouse duodenum, resulting in cytotoxicity with consequent regenerative proliferation and ultimately tumor development. Forestomach lesions secondary to cytotoxicity are also induced. Dogs have stomachs similar to humans and show no evidence of gastrointestinal toxicity or tumor formation at exposure levels at least as high as rodents. The data support a MOA in mice involving cytotoxicity and regenerative proliferation. Based on MOA analysis and assessment of human relevance, folpet, like captan, another trichloromethylthio-related fungicide with similar toxic and carcinogenic effects, is not likely to be a human carcinogen at dose levels that do not cause cytotoxicity and regenerative proliferation.

Folpet and captan are fungicides whose genotoxicity depends on their chemical reaction with thiols. Multiple mutagenicity tests have been conducted on these compounds due to their positive activity in vitro and their association with gastrointestinal tumors in mice. A review of the collective data shows that these compounds have in vitro mutagenic activity but are not genotoxic in vivo. This dichotomy is primarily due to the rapid degradation of folpet and captan in the presence of thiol-rich matrices typically found in vivo. Genotoxicity has not been found in the duodenum, the mouse tumor target tissue. It is concluded that folpet like captan presents an unlikely risk of genotoxic effects in humans.

On 24 November 2004 EPA changed the cancer classification of captan from a 'probable human carcinogen' (Category B2) to 'not likely' when used according to label directions. The new cancer classification considers captan to be a potential carcinogen at prolonged high doses that cause cytotoxicity and regenerative cell hyperplasia. These high doses of captan are many orders of magnitude above those likely to be consumed in the diet, or encountered by individuals in occupational or residential settings. This revised cancer classification reflects EPA's implementation of their new cancer guidelines. The procedures involved in the reclassification effort were agreed upon with EPA and involved an Independent Transparent Review as it related to four components that formed the basis of the original 1986 B2 classification: mouse tumors; rat tumors; mutagenicity; and structural similarity to other carcinogens. A Peer Review Panel organized and administered by Toxicology Excellence for Risk Assessment (TERA) met on 2-3 September 2003. The Panel concluded that captan acted through a non-mutagenic threshold mode of action that required prolonged irritation of the duodenal villi as the initial key event. EPA's Cancer Assessment Review Committee (CARC) met on 9 June 2004 and endorsed the Peer Review findings. EPA intended to have the FIFRA Scientific Advisory Panel (SAP) consider the basis for this reclassification but found the science was robust and judged that a SAP review was not warranted. Using the revised classification, the margin of exposure is approximately 1,200,000, supporting the 'not likely' characterization.

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Under the Food Quality Protection Act (FQPA) of 1996 (Act), the United States Environmental Protection Agency (EPA) is mandated to conduct cumulative risk assessment on pesticides that act through a common mechanism of toxicity. Incumbent on the Agency is the development of sound scientific principles upon which to evaluate compounds for the presence of a common mechanism. Using the currently available draft guidance criteria, this paper employs five fungicides of the same general class, typified by captan, to evaluate both the criteria and the available scientific data. Captan and folpet are two chloroalkylthio fungicides currently registered with EPA under Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) for agricultural use. As such, these compounds are subject to the provisions of FQPA. Three additional fungicidal compounds—dichlofluanid, tolylfluanid, and captafol—are not registered for use in the United States; however, these five compounds have chemical structure and biological toxicity similarities and differences that permit their utility as test cases to determine what the EPA would conclude, with regard to common mechanism, if these draft guidelines were applied to these compounds. The results of the analyses are consistent and support the conclusion that captan and folpet share a common mode of toxicity for mouse duodenal tumors as defined in the Act. This common mode of toxicity is not shared by dichlofluanid, tolylfluanid, or captafol. The basis for concluding a common mechanism exists between captan and folpet. They include 1. Structural Similarity—The compounds are structural analogs having the identical biologically active moiety (i.e., the-SCCl3 side chain). 2. Mechanisms of Pesticidal Action—The compounds have the same mechanism of action. The overwhelming body of evidence suggests they are active because of their reactions with thiols. Both compounds, in reacting with thiols, produce similar degradates. Differences in rates of reaction are attributable to physical-chemical properties of the two compounds. 3. General Mechanisms of Mammalian Toxicity—The compounds induce mammalian toxicity through the same mechanism that is responsible for their pesticidal action, reactions with thiols. Another, albeit less likely, mechanism (for both compounds) is cross-Unking of proteins with DNA, although the extremely short half-lives of these compounds (seconds) argues against this possibility. 4. Sites of Action—Both compounds express their primary toxicity as local rather than systemic effects. 5. Common Toxic Endpoint—These two compounds induce gastrointestinal tumors (in mice only). 6. Mode of Action—Both compounds express their common toxic endpoint through a nongenotoxic, compensatory proliferation mechanism. 7. Specificity of Action—For both compounds, the majority of tumors appear in the duodenum. Furthermore, these tumors are induced only in mice. Repeated carcinogenicity testing suggests that rats are refractive to the effects of captan and folpet. The significantly faster hydrolytic rate for folpet at the lower pH values (e.g., increased 8-fold at pH 5) encountered in the stomach is believed to account for the tumors of the stomach observed with folpet and not captan. 8. Other Toxic Endpoints—For other toxic endpoints where comparative data are available, captan and folpet show similar patterns of toxicity (e.g., mutagenicity, skin sensitization, and acute toxicity).

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