Risk Assessment and Alternatives Assessment: Comparing Two Methodologies.

The selection and use of chemicals and materials with less hazardous profiles reflects a paradigm shift from reliance on risk minimization through exposure controls to hazard avoidance. This article introduces risk assessment and alternatives assessment frameworks in order to clarify a misconception that alternatives assessment is a less effective tool to guide decision making, discusses factors promoting the use of each framework, and also identifies how and when application of each framework is most effective. As part of an assessor's decision process to select one framework over the other, it is critical to recognize that each framework is intended to perform different functions. Although the two frameworks share a number of similarities (such as identifying hazards and assessing exposure), an alternatives assessment provides a more realistic framework with which to select environmentally preferable chemicals because of its primary reliance on assessing hazards and secondary reliance on exposure assessment. Relevant to other life cycle impacts, the hazard of a chemical is inherent, and although it may be possible to minimize exposure (and subsequently reduce risk), it is challenging to assess such exposures through a chemical's life cycle. Through increased use of alternatives assessments at the initial stage of material or product design, there will be less reliance on post facto risk-based assessment techniques because the potential for harm is significantly reduced, if not avoided, negating the need for assessing risk in the first place.

Derivation of a No-Significant-Risk-Level (NSRL) for diethanolamine (DEA).

Diethanolamine (DEA) has been listed on the State of California's Proposition 65 List. This listing is based in part on tumors reported in a National Toxicology Program (NTP) 2-year dermal carcinogenicity study in mice which found clear evidence of carcinogenic activity in B6C3F1 mice based on increased incidences of liver neoplasms in both sexes, and increased incidences of renal tubule neoplasms in males. Although considerable controversy exists on the relevance of the NTP study to humans, industries are obligated to comply with the Proposition 65 labeling requirement and drinking water discharge prohibition, unless they are able to demonstrate that DEA levels in their products are below a specific No Significant Risk Level (NSRL). The State of California has not published an NSRL for DEA. In this article, a NSRL of 5.6 µg/day and a life-stage-adjusted NSRL(adj) of 1.4 µg/day are derived from the NTP carcinogenicity study using a benchmark dose modeling method based on the incidence of hepatocellular carcinomas in female mice, in accordance with the guidelines of California EPA.

Exposure to Pb, Cd, and As mixtures potentiates the production of oxidative stress precursors: 30-day, 90-day, and 180-day drinking water studies in rats.

Exposure to chemical mixtures is a common and important determinant of toxicity and is of particular concern due to their appearance in sources of drinking water. Despite this, few in vivo mixture studies have been conducted to date to understand the health impact of chemical mixtures compared to single chemicals. Interactive effects of lead (Pb), cadmium (Cd) and arsenic (As) were evaluated in 30-, 90-, and 180-day factorial design drinking water studies in rats designed to test the hypothesis that ingestion of such mixtures at individual component Lowest-Observed-Effect-Levels (LOELs) results in increased levels of the pro-oxidant delta aminolevulinic acid (ALA), iron, and copper. LOEL levels of Pb, Cd, and As mixtures resulted in the increased presence of mediators of oxidative stress such as ALA, copper, and iron. ALA increases were followed by statistically significant increases in kidney copper in the 90- and 180-day studies. Statistical evidence of interaction was identified for six biologically relevant variables: blood delta aminolevulinic acid dehydratase (ALAD), kidney ALAD, urinary ALA, urinary iron, kidney iron, and kidney copper. The current investigations underscore the importance of considering interactive effects that common toxic agents such as Pb, Cd, and As may have upon one another at low-dose levels. The interactions between known toxic trace elements at biologically relevant concentrations shown here demonstrate a clear need to rigorously review methods by which national/international agencies assess health risks of chemicals, since exposures may commonly occur as complex mixtures.

Therapeutic dose as the point of departure in assessing potential health hazards from drugs in drinking water and recycled municipal wastewater.

The detection of drugs in drinking water sources has raised questions related to safety. In the absence of regulatory or other official guidance, water utilities are faced with a problem of which drugs should be monitored and the detection limits that should be required. The US FDA summarizes data required for drug approval and post marketing adverse reaction reporting. The use of these data as a means of arriving at concentrations in water where adverse health effects are minimal or non-existent was explored. The minimum therapeutic dose was assumed an appropriate point of departure. Appropriate uncertainty factors could be applied depending upon the qualitative and quantitative nature of the data that are available. Assumptions inherent in US FDA's approval of drugs for use in subsets of the population relative to the broader concerns that arise for exposures of the entire population had to be considered. Additional questions are; whether the drug under consideration is carcinogenic, carries pregnancy and lactation warnings, approval for limited vs. chronic use, exposures to multiple compounds that could act in additive or synergistic ways, and the seriousness of toxicities that are observed. Aside from these considerations, a combined uncertainty factor of 1000 appeared adequate.

Derivation of a No significant risk level (NSRL) for acrylamide.

Acrylamide is included on the State of California's Proposition 65 list as a carcinogen. Acrylamide is found in cigarette smoke and in many types of foods, including breads, cereals, coffee, cookies, French fries, and potato chips. In 1990, California's Office of Environmental Health Hazard Assessment (OEHHA) established a no significant risk level (NSRL) of 0.2 µg/day for acrylamide. Since then, multiple cancer studies have been published. In this report, we developed an updated NSRL for acrylamide. Using benchmark dose modeling and a weight-of-evidence, non-threshold approach to identify the most sensitive species, cancer slope factors (CSFs) were derived based on combined incidences of statistically significant neoplastic lesions in the Harderian gland, lung, and stomach in male mice. We then used a toxicokinetic (TK)-based scaling approach to convert the animal CSF to a human equivalent CSF, which served as the basis for the NSRL of 1.1 µg/day at the cancer risk level of 1 in 100,000. This NSRL can be used in quantitative exposure assessments to assess compliance with Proposition 65 to ascertain either the need for or exemption from the Proposition 65 labeling requirement and drinking water discharge prohibition.

Qualitative approach to comparative exposure in alternatives assessment.

Most alternatives assessments (AAs) published to date are largely hazard-based rankings, thereby ignoring potential differences in human and/or ecosystem exposures; as such, they may not represent a fully informed consideration of the advantages and disadvantages of possible alternatives. Building on the 2014 US National Academy of Sciences recommendations to improve AA decisions by including comparative exposure assessment into AAs, the Health and Environmental Sciences Institute's (HESI) Sustainable Chemical Alternatives Technical Committee, which comprises scientists from academia, industry, government, and nonprofit organizations, developed a qualitative comparative exposure approach. Conducting such a comparison can screen for alternatives that are expected to have a higher or different routes of human or environmental exposure potential, which together with consideration of the hazard assessment, could trigger a higher tiered, more quantitative exposure assessment on the alternatives being considered, minimizing the likelihood of regrettable substitution. This article outlines an approach for including chemical ingredient- and product-related exposure information in a qualitative comparison, including ingredient and product-related parameters. A classification approach was developed for ingredient and product parameters to support comparisons between alternatives as well as a methodology to address exposure parameter relevance and data quality. The ingredient parameters include a range of physicochemical properties that can impact routes and magnitude of exposure, whereas the product parameters include aspects such as product-specific exposure pathways, use information, accessibility, and disposal. Two case studies are used to demonstrate the application of the methodology. Key learnings and future research needs are summarized. Integr Environ Assess Manag 2018;00:000-000. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Enhancing nonhuman primate care and welfare through the use of positive reinforcement training.

Nonhuman primates are excellent subjects for the enhancement of care and welfare through training. The broad range of species offers tremendous behavioral diversity, and individual primates show varying abilities to cope with the stressors of captivity, which differ depending on the venue. Biomedical facilities include small single cages, pair housing, and breeding corrals with large social groups. Zoos have social groupings of differing sizes, emphasizing public display and breeding. Sanctuaries have nonbreeding groups of varying sizes and often of mixed species. In every venue, the primary objective is to provide good quality care, with minimal stress. Positive reinforcement training improves care and reduces stress by enlisting a primate's voluntary cooperation with targeted activities, including both husbandry and medical procedures. It can also improve socialization, reduce abnormal behaviors, and increase species-typical behaviors. This article reviews the results already achieved with positive reinforcement training and suggests further possibilities for enhancing primate care and welfare.

Advancing alternatives analysis: The role of predictive toxicology in selecting safer chemical products and processes.

Alternatives analysis (AA) is a method used in regulation and product design to identify, assess, and evaluate the safety and viability of potential substitutes for hazardous chemicals. It requires toxicological data for the existing chemical and potential alternatives. Predictive toxicology uses in silico and in vitro approaches, computational models, and other tools to expedite toxicological data generation in a more cost-effective manner than traditional approaches. The present article briefly reviews the challenges associated with using predictive toxicology in regulatory AA, then presents 4 recommendations for its advancement. It recommends using case studies to advance the integration of predictive toxicology into AA, adopting a stepwise process to employing predictive toxicology in AA beginning with prioritization of chemicals of concern, leveraging existing resources to advance the integration of predictive toxicology into the practice of AA, and supporting transdisciplinary efforts. The further incorporation of predictive toxicology into AA would advance the ability of companies and regulators to select alternatives to harmful ingredients, and potentially increase the use of predictive toxicology in regulation more broadly. Integr Environ Assess Manag 2017;13:915-925. © 2017 SETAC.

Training techniques to enhance the care and welfare of nonhuman primates.

Nonhuman primates are excellent subjects for the enhancement of care and welfare through training. The application of positive reinforcement techniques to specific aspects of the management of captive nonhuman primates spans a wide range of species, social contexts, and housing situations (eg, laboratories, zoos, and sanctuaries). There is an increased interest from regulatory and accrediting agencies to insure improved conditions for captive nonhuman primates, apparent by the various standard guidelines, accreditation standards, and protocols available for the 3 primary types of nonhuman primate holding facilities.

Oxidative stress induced by lead, cadmium and arsenic mixtures: 30-day, 90-day, and 180-day drinking water studies in rats: an overview.

Humans are frequently exposed to combinations of lead (Pb), cadmium (Cd) and Arsenic (As) but there is a paucity of actual data on the molecular effects of these agents at low dose levels. The present factorial design studies were undertaken in rats to examine the effects of these agents at LOEL dose levels on a number of molecular parameters of oxidative stress in hematopoietic and renal organ systems following oral exposure in drinking water at 30, 90 and 180 day time points. Results of these studies demonstrated dynamic, time-dependent alterations in both molecular targets and inducible oxidative stress protective systems in target cell populations. In general, cellular protective systems, which protected against oxidative damage at the 90 day time point, appeared to be finite such that molecular manifestations of oxidative stress became statistically significant at the 180 day time point for several of the combination exposure groups. These data demonstrate the importance of duration of exposure in assessing the toxic potential of Pb, Cd and As mixtures at low dose levels.

Human health risk assessment of 2-mercaptobenzothiazole in drinking water.

2-Mercaptobenzothiazole (MBT) is used as a vulcanization accelerator in rubber products that come into contact with potable drinking water. When such products are evaluated for contact with potable water and submitted for ANSI/NSF Standard 61 certification, any chemical extracting from these products must be below an appropriate action level of exposure. As defined by Standard 61, a total allowable concentration (TAC) is the maximum concentration of a nonregulated contaminant allowed in a public drinking water supply, and the single product allowable concentration (SPAC) is 10% of the TAC. Currently, MBT has a TAC of 40 microg/L and a SPAC of 4 microg/L. A comprehensive health effects evaluation of MBT was performed to determine whether these action levels should be revised. Epidemiological investigations indicate that workers occupationally exposed to MBT have an increased risk of death from bladder cancer. Genotoxicity investigations in bacterial and mammalian test systems provide some evidence indicating that MBT has the potential to induce mutations and chromosomal aberrations. Toxicity studies in rats and mice chronically exposed to MBT identified increases in various tumours, such as adrenal gland tumours, pituitary gland tumours, liver tumours and renal pelvis tumours. The biological significance of most of these tumours is questionable due to a variety of factors, such as a lack of dose-response between tumour incidence and dose, and the effect of test article vehicle (corn oil) upon tumour rates. Potential human health effects of exposure to MBT can be predicted from an NTP 2-year cancer study in rats, as well as epidemiological investigations in occupationally exposed workers. A comprehensive review of the epidemiological and toxicological dataset for MBT indicates that the induction of renal pelvis transitional cell tumours is the most sensitive and relevant health effects endpoint upon which to base a revised TAC and SPAC. A multistage model was used to extrapolate to low-dose MBT exposures due to the genotoxicity and clastogenicity of MBT. A TAC of 600 microg/L was derived for MBT, and was based upon an LED10 of 157.681 mg/kg per day. A SPAC of 60 microg/L was derived by multiplying the revised TAC by 0.10, and rounding to one significant figure. These revised action levels are based upon the most sensitive health effects endpoint, as well as current cancer risk assessment methodology.