A systematic evidence map for the evaluation of noncancer health effects and exposures to polychlorinated biphenyl mixtures.

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty.

Health Effects of Naphthalene Exposure: A Systematic Evidence Map and Analysis of Potential Considerations for Dose-Response Evaluation.

BACKGROUND: Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment. OBJECTIVES: We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene. METHODS: Human and animal health effect studies and physiologically based pharmacokinetic (PBPK) models were identified from a literature search based on populations, exposures, comparators, and outcomes (PECO) criteria. Human and animal studies meeting PECO criteria were refined to a smaller subset considered most informative for deriving chronic reference value(s), which are preferred for assessing risk to the general public. This subset was evaluated for risk of bias and sensitivity, and the suitability of each study for dose-response analysis was qualitatively assessed. Lowest observed adverse effect levels (LOAELs) were extracted and summarized. Other potentially relevant studies (e.g., mechanistic and toxicokinetic studies) were tracked as supplemental information but not evaluated further. Existing reference values for naphthalene are also summarized. RESULTS: We identified 26 epidemiology studies and 16 animal studies that were considered most informative for further analysis. Eleven PBPK models were identified. The available epidemiology studies generally had significant risk of bias and/or sensitivity concerns and were mostly found to have low suitability for dose-response analysis due to the nature of the exposure measurements. The animal studies had fewer risk of bias and sensitivity concerns and were mostly found to be suitable for dose-response analysis. CONCLUSION: Although both epidemiological and animal studies of naphthalene provide weight of evidence for hazard identification, the available animal studies appear more suitable for reference value derivation. PBPK models and mechanistic and toxicokinetic data can be applied to extrapolate these animal data to humans, considering mode of action and interspecies metabolic differences. https://doi.org/10.1289/EHP7381.

Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies.

BACKGROUND: Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of phthalates, but there is emerging evidence that DEP may be associated with other types of health effects. OBJECTIVE: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DEP or its primary metabolite, monoethyl phthalate (MEP). METHODS: A literature search was conducted in online scientific databases (PubMed, Web of Science, Toxline, Toxcenter) and Toxic Substances Control Act Submissions, augmented by review of online regulatory sources as well as forward and backward searches. Studies were selected for inclusion using PECO (Population, Exposure, Comparator, Outcome) criteria. Studies were evaluated using criteria defined a priori for reporting quality, risk of bias, and sensitivity using a domain-based approach. Evidence was synthesized by outcome and life stage of exposure, and strength of evidence was summarized into categories of robust, moderate, slight, indeterminate, or compelling evidence of no effect, using a structured framework. RESULTS: Thirty-four experimental studies in animals were included in this analysis. Although no effects on androgen-dependent male reproductive development were observed following gestational exposure to DEP, there was evidence including effects on sperm following peripubertal and adult exposures, and the overall evidence for male reproductive effects was considered moderate. There was moderate evidence that DEP exposure can lead to developmental effects, with the major effect being reduced postnatal growth following gestational or early postnatal exposure; this generally occurred at doses associated with maternal effects, consistent with the observation that DEP is not a potent developmental toxicant. The evidence for liver effects was considered moderate based on consistent changes in relative liver weight at higher dose levels; histopathological and biochemical changes indicative of hepatic effects were also observed, but primarily in studies that had significant concerns for risk of bias and sensitivity. The evidence for female reproductive effects was considered slight based on few reports of statistically significant effects on maternal body weight gain, organ weight changes, and pregnancy outcomes. Evidence for cancer and effects on kidney were judged to be indeterminate based on limited evidence (i.e., a single two-year cancer bioassay) and inconsistent findings, respectively. CONCLUSIONS: These results suggest that DEP exposure may induce androgen-independent male reproductive toxicity (i.e., sperm effects) as well as developmental toxicity and hepatic effects, with some evidence of female reproductive toxicity. More research is warranted to fully evaluate these outcomes and strengthen confidence in this database.

A Physiologically Based Pharmacokinetic Model for Naphthalene With Inhalation and Skin Routes of Exposure.

Naphthalene, a volatile organic compound present in moth repellants and petroleum-based fuels, has been shown to induce toxicity in mice and rats during chronic inhalation exposures. Although simpler default methods exist for extrapolating toxicity points of departure from animals to humans, using a physiologically based pharmacokinetic (PBPK) model to perform such extrapolations is generally preferred. Confidence in PBPK models increases when they have been validated using both animal and human in vivo pharmacokinetic (PK) data. A published inhalation PBPK model for naphthalene was previously shown to predict rodent PK data well, so we sought to evaluate this model using human PK data. The most reliable human data available come from a controlled skin exposure study, but the inhalation PBPK model does not include a skin exposure route; therefore, we extended the model by incorporating compartments representing the stratum corneum and the viable epidermis and parameters that determine absorption and rate of transport through the skin. The human data revealed measurable blood concentrations of naphthalene present in the subjects prior to skin exposure, so we also introduced a continuous dose-rate parameter to account for these baseline blood concentration levels. We calibrated the three new parameters in the modified PBPK model using data from the controlled skin exposure study but did not modify values for any other parameters. Model predictions then fell within a factor of 2 of most (96%) of the human PK observations, demonstrating that this model can accurately predict internal doses of naphthalene and is thus a viable tool for use in human health risk assessment.

Use of the Adverse Outcome Pathway (AOP) framework to evaluate species concordance and human relevance of Dibutyl phthalate (DBP)-induced male reproductive toxicity.

Dibutyl phthalate (DBP) is a phthalate ester used as a plasticizer, and solvent. Studies using rats consistently report that DBP exposure disrupts normal development of the male reproductive system in part via inhibition of androgen synthesis. However, studies using xenograft models report that in human fetal testis DBP exposure is unlikely to impair testosterone synthesis. These results question the validity of the rat model for assessment of male reproductive effects caused by DBP. The Adverse Outcome Pathway (AOP) framework was used to evaluate the available evidence for DBP-induced toxicity to the male reproductive system. Three relevant biological elements were identified: 1) fetal rats are more sensitive than other rodents and human fetal xenografts to DBP-induced anti-androgenic effects, 2) DBP-induced androgen-independent adverse outcomes are conserved amongst different mammalian models and human fetal testis xenografts, and 3) DBP-induced anti-androgenic effects are conserved in different mammalian species when exposure occurs during postnatal life stages.

Proposed Key Characteristics of Male Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Evidence in Human Health Hazard Assessments.

BACKGROUND: Assessing chemicals for their potential to cause male reproductive toxicity involves the evaluation of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in hazard identification and evidence integration, the process of identifying, screening and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods and the variety of known and proposed pathways for chemical-induced toxicity. Ten key characteristics of carcinogens provide a valuable tool for organizing and assessing chemical-specific data by potential mechanisms for cancer-causing agents. However, such an approach has not yet been developed for noncancer adverse outcomes. OBJECTIVES: The objective in this study was to identify a set of key characteristics that are frequently exhibited by exogenous agents that cause male reproductive toxicity and that could be applied for identifying, organizing, and summarizing mechanistic evidence related to this outcome. DISCUSSION: The identification of eight key characteristics of male reproductive toxicants was based on a survey of known male reproductive toxicants and established mechanisms and pathways of toxicity. The eight key characteristics can provide a basis for the systematic, transparent, and objective organization of mechanistic evidence relevant to chemical-induced effects on the male reproductive system. https://doi.org/10.1289/EHP5045.

Hazards of diisobutyl phthalate (DIBP) exposure: A systematic review of animal toxicology studies.

BACKGROUND: Biomonitoring studies indicate a trend towards increased human exposure to diisobutyl phthalate (DIBP), a replacement for dibutyl phthalate (DBP). Recent reviews have found DIBP to be a male reproductive toxicant, but have not evaluated other hazards of DIBP exposure. OBJECTIVE: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DIBP or the primary metabolite, monoisobutyl phthalate (MIBP). METHODS: A literature search was conducted in four online scientific databases [PubMed, Web of Science, Toxline, and Toxic Substances Control Act Test Submissions 2.0 (TSCATS2)], and augmented by review of regulatory sources as well as forward and backward searches. Studies were identified for inclusion based on defined PECO (Population, Exposure, Comparator, Outcome) criteria. Studies were evaluated using criteria defined a priori for reporting quality, risk of bias, and sensitivity using a domain-based approach. Evidence was synthesized by outcome and life stage of exposure, and strength of evidence was summarized into categories of robust, moderate, slight, indeterminate, or compelling evidence of no effect, using a structured framework. RESULTS: Nineteen toxicological studies in rats or mice met the inclusion criteria. There was robust evidence that DIBP causes male reproductive toxicity. Male rats and mice exposed to DIBP during gestation had decreased testosterone and adverse effects on sperm or testicular histology, with additional phthalate syndrome effects observed in male rats. There was also evidence of androgen-dependent and -independent male reproductive effects in rats and mice following peripubertal or young adult exposure to DIBP or MIBP, but confidence was reduced because of concerns over risk of bias and sensitivity in the available studies. There was also robust evidence that DIBP causes developmental toxicity; specifically, increased post-implantation loss and decreased pre- and postnatal growth. For other hazards, evidence was limited by the small number of studies, experimental designs that were suboptimal for evaluating outcomes, and study evaluation concerns such as incomplete reporting of methods and results. There was slight evidence for female reproductive toxicity and effects on liver, and indeterminate evidence for effects on kidney and cancer. CONCLUSION: Results support DIBP as a children's health concern and indicate that male reproductive and developmental toxicities are hazards of DIBP exposure, with some evidence for female reproductive and liver toxicity. Data gaps include the need for more studies on male reproductive effects following postnatal and adult exposure, and studies to characterize potential hormonal mechanisms in females.

An object-oriented Bayesian network approach for establishing swine manure-borne natural estrogenic compounds budget.

A facility-wide estrogen budget model was developed to assess the excretion of natural estrogens by swine in a commercial swine farrowing concentrated animal feeding operations (CAFO) in North Carolina, using an object-oriented Bayesian network (OOBN) approach. The OOBN model is the combination of twelve objects of Bayesian network models, which characterize the estrogen budget flows based on the sow reproductive cycle (i.e., pre-estrus, estrus, and lactation) for the three natural estrogen types [estrone (E1), 17ß-estradiol (E2), and estriol (E3)] within each barn. This OOBN model provides a mechanism to quantify the levels of the natural estrogens and their probabilistic distributions with regard to estrogen type, waste sources such as urine, feces, and recycling lagoon slurry, and animal reproductive status. Moreover, the OOBN model allows us to assess the overall contribution of natural estrogen compounds from each operational unit of the CAFO, while accounting for the uncertainties. Results from the OOBN model indicate a rank order of lactating sows > gestating sows > breeding sows in terms of contribution of estrogen loads to the total natural estrogen budget. As to estrogen type, E1 was found as the major estrogen metabolite with the summed concentrations of urine, feces, and flushing slurry wastes exceeding 3000 ng/l > 90% of the time. As to waste sources, the flushing slurry waste was found to be a major contributor of the estrogen budget compared with urine and feces wastes from barn animals.