Stewardship challenges abortion: A proposed means to mitigate abortion's social divisiveness.

Since 1973 the legislated constitutional right to abortion has produced a political dichotomy (anti-abortion versus pro-abortion) within the United States, even while witnessing a gradual decline in the rate of abortions. A third paradigm, moral stewardship, is advanced as an effective means to ameliorate this social divisiveness. Incorporating the concept of stewardship into deliberations of pregnancy termination would require recognition, through fact-based education programs, of the life circumstances that prompt the consideration to terminate a pregnancy. Based on collective responsibility, policies, and programs are needed to foster social justice for parents and for the offspring brought to term, without creating excessive burdens on women faced with an unwanted pregnancy. Moral stewardship is perceived as humanitarian to family and community and advantageous to society overall. It also offers a serious opportunity to reshape our society from divisiveness to inclusiveness, and to guide science policy judgment that enhances and strengthens social justice. Lay summary: Differing opinions over the ethics of human abortion have been legion since Roe v. Wade (1973). The disputes between pro- and anti-abortion factions have segregated society with few improvements in social justice. This study offers an alternative approach, one capable of social assimilation and justice for unwanted offspring and pregnant mothers bearing them. It promotes moral stewardship toward the unborn whose humanity and personhood are recognized genetically and supported philosophically by long-standing ethical principles. Stewardship incorporates all people at all levels of society based on collective responsibility, supported by government policies, yet not restricting a mother's choices for the future of her unborn offspring.

Derivation of a reference dose and drinking water equivalent level for 1,2,3-trichloropropane.

In some US potable water supplies, 1,2,3-trichloropropane (TCP) has been present at ranges of non-detect to less than 100 ppb, resulting from past uses. In subchronic oral studies, TCP produced toxicity in kidneys, liver, and other tissues. TCP administered by corn oil gavage in chronic studies produced tumors at multiple sites in rats and mice; however, interpretation of these studies was impeded by substantial premature mortality. Drinking water equivalent levels (DWELs) were estimated for a lifetime of consumption by applying biologically-based safety/risk assessment approaches, including Monte Carlo techniques, and with consideration of kinetics and modes of action, to possibly replace default assumptions. Internationally recognized Frameworks for human relevance of animal data were employed to interpret the findings. Calculated were a reference dose (=39 microg/kg d) for non-cancer and Cancer Values (CV) (=10-14 microg/kg d) based on non-linear dose-response relationships for mutagenicity as a precursor of cancer. Lifetime Average Daily Intakes (LADI) are 3130 and 790-1120 microg/person-d for non-cancer and cancer, respectively. DWELs, estimated by applying a relative source contribution (RSC) of 50% to the LADIs, are 780 and 200-280 microg/L for non-cancer and cancer, respectively. These DWELs may inform establishment of formal/informal guidelines and standards to protect public health.

Development of a physiologically-based toxicokinetic model of acrylamide and glycidamide in rats and humans.

Physiologically-based toxicokinetic ("pharmacokinetic") (PBPK or PBTK) modeling can be used as a tool to compare internal doses of acrylamide (AA) and its metabolite glycidamide (GA) in humans and rats. An earlier PBTK model for AA and GA in rats was refined and extended to humans based on new data. With adjustments to the previous parameters, excellent fits to a majority of the data for male Fisher 344 rats were obtained. Kinetic parameters for the human model were estimated based on fit to available human data for urinary metabolites of AA, and levels of hemoglobin adducts of AA and GA measured in studies in which human volunteers ingested known doses of AA. The simulations conducted with the rat and human models predicted that rats and humans ingesting comparable levels of AA (in mg/kg day) would have similar levels of GA in blood and tissues. This finding stands in contrast to the default approach that assumes a 3.2-fold increase in human risk due to pharmacokinetic differences between rats and humans. This model was used in a companion paper to estimate safe levels of ingested AA.

Estimation of safe dietary intake levels of acrylamide for humans.

Acrylamide (AA), a human neurotoxicant and rat tumorigen, is produced in starchy foods when cooked. AA is also an industrial chemical used in polyacrylamide production. A safety evaluation of ingested AA by humans was conducted using a newly developed, state-of-the-art physiologically-based toxicokinetic (PBPK or PBTK) model to compare internal doses of AA and its metabolite glycidamide (GA) in humans and rats. Based on modes of action (MoA), a nonlinear dose-response approach was applied for neurotoxicity (non-genotoxicity) and carcinogenicity (mixed: genotoxicity and epigenetic MoA). Tolerable daily intake (TDI) for neurotoxicity from AA was estimated to be 40 microg/kg-day; TDIs for cancer were estimated to be 2.6 and 16 microg/kg-day based on AA or GA, respectively. Margins of exposure (MoE) were calculated for average AA consumers to be 300 and 500 based on AA and GA, respectively; for cancer, the MoE for average AA consumers was estimated to be 200 and 1200 based on AA and GA, respectively. For high consumers of AA, MoEs were somewhat less.

Human uptake of persistent chemicals from contaminated soil: PCDD/Fs and PCBs.

Trace amounts of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are ubiquitous in the environment. Because of industrial activity, other human activities, and accidents, higher concentrations of these chemicals may be present in soil, in residential and recreational areas. Human uptake of these chemicals from such soils has been assumed by regulators, and people contacting such soils may be concerned about potential adverse health effects. Accordingly, clean up levels have been set by state and federal agencies. Whether and to what extent humans actually take up these chemicals from soil is the focus of this review. Since humans are also exposed to PCDD/Fs and PCBs in food and air, their concentrations in these media are presented. We find that their presence in soils is unlikely to increase human body burdens.

Derivation of a drinking water equivalent level (DWEL) related to the maximum contaminant level goal for perfluorooctanoic acid (PFOA), a persistent water soluble compound.

Water soluble compounds persistent in humans and the environment pose a challenge for estimating safe levels in tap water. A viable approach to estimate a drinking water equivalent level (DWEL) for perfluorooctanoic acid (PFOA) was applied to its extensive relevant information from human and laboratory animal studies. PFOA has been identified at 3.5 microg/L (mean) in tap water in proximity to a manufacturing facility; however, in most supplies, the levels were below 7.5 ng/L (usual limit of detection). PFOA has an average half-life in humans of 3.5years. From animal studies, PFOA is considered a possible hepatotoxicant and developmental toxicant for humans. Based on two chronic studies, PFOA was judged to be a possible human carcinogen, whose mode-of-action was likely to be related to receptor activation but not genotoxicity. The Benchmark Dose-Uncertainty Factor approach was selected for dose-response for noncancer and cancer. Based on internal dose of PFOA, the DWEL protective against cancer is 7.7 microgPFOA/L tap water, and the noncancer DWELs range from 0.88 to 2.4 microg/L. These DWELs can be considered a reliable, albeit conservative, basis to set a Maximum Concentration Level Goal under the US Safe Drinking Water Act.

Updated weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products.

Disinfection by-products (DBP) are produced when water is treated with chemical disinfectants. Some toxicological and epidemiological studies suggest an association between DBP exposure and adverse reproductive and developmental effects. In a previous critical review, [Graves, C.G., Matanoski, G.M., Tardiff, R.G., 2001. Weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products: a critical review. Regul. Toxicol. Pharmacol. 34, (2) 103-124] evaluated the weight of evidence for this exposure and these effects. This investigation updates the previous evaluation and considers all toxicological and epidemiological evidence since the earlier review and reassesses the weight-of-evidence for all of the data on the various effects, outcome by outcome. The updated toxicity weight of evidence found little indication of previously unreported reproductive or developmental toxicity. In particular, the recently published findings of an exceptionally well conducted cohort study of broad scope found no impact of chlorination by-products on the highly controversial outcome of spontaneous abortion, unlike predecessor studies of more limited methodology, leading the authors to recommend no further epidemiologic pursuit for this hypothesis since the cohort was scrutinized very closely and dispelled any concern of such an association. The updated epidemiologic weight of evidence demonstrated that no association with DBP exposure exists for over a dozen outcomes including low and very low birth weight, preterm delivery, some specific congenital anomalies, and neonatal death. The analysis found inconsistent or very weak results for all congenital anomalies/birth defects, all central nervous system anomalies, neural tube defects, and spontaneous abortion. As in the previous article, the updated weight of evidence suggested a positive association with DBP exposure and some measure of growth retardation such as intrauterine growth retardation, small for gestational age, term low birth weight, and small body length or head circumference. Exposure assessment in most epidemiological studies remains inadequate to definitively demonstrate any association of small magnitude.

Harmonization of thresholds for primary skin irritation from results of human repeated insult patch tests and laboratory animal skin irritation tests.

Classification of a chemical or chemical product as a primary skin irritant using laboratory animal tests has been defined rigorously and codified in Consumer Products Safety Commission (CPSC) regulations. However, no regulatory agency, including the CPSC, has defined a primary skin irritant threshold for human repeat insult patch tests (RIPTs) that are typically conducted on products, such as cosmetics, anticipated to come into direct contact with humans. Further more, the protocols for animal and human tests are significantly different, as are the schemes for grading responses. Consequently, comparing the results of one type of test with those from the other type has proved to be difficult. In this short communication, we propose a procedure to harmonize the results from these two types of skin irritation tests and suggest that a score of "5" in animal tests, considering 24-h results on unabraded skin, is equivalent to a score of "3" in human RIPTs.