Assessment of associations between inhaled formaldehyde and lymphohematopoietic cancer through the integration of epidemiological and toxicological evidence with biological plausibility.

Formaldehyde is recognized as carcinogenic for the portal of entry sites, though conclusions are mixed regarding lymphohematopoietic (LHP) cancers. This systematic review assesses the likelihood of a causal relationship between formaldehyde and LHP cancers by integrating components recommended by NASEM. Four experimental rodent bioassays and 16 observational studies in humans were included following the implementation of the a priori protocol. All studies were assessed for risk of bias (RoB), and meta-analyses were conducted on epidemiological studies, followed by a structured assessment of causation based on GRADE and Bradford Hill. RoB analysis identified systemic limitations precluding confidence in the epidemiological evidence due to inadequate characterization of formaldehyde exposure and a failure to adequately adjust for confounders or effect modifiers, thus suggesting that effect estimates are likely to be impacted by systemic bias. Mixed findings were reported in individual studies; meta-analyses did not identify significant associations between formaldehyde inhalation (when measured as ever/never exposure) and LHP outcomes, with meta-SMRs ranging from 0.50 to 1.51, depending on LHP subtype. No associations with LHP-related lesions were reported in reliable animal bioassays. No biologically plausible explanation linking the inhalation of FA and LHP was identified, supported primarily by the lack of systemic distribution and in vivo genotoxicity. In conclusion, the inconsistent associations reported in a subset of the evidence were not considered causal when integrated with the totality of the epidemiological evidence, toxicological data, and considerations of biological plausibility. The impact of systemic biases identified herein could be quantitatively assessed to better inform causality and use in risk assessment.

Systematic review of the human health hazards of propylene dichloride.

Propylene dichloride (PDC) is a chlorinated substance used primarily as an intermediate in basic organic chemical manufacturing. The United States Environmental Protection Agency (EPA) is currently evaluating PDC as a high-priority substance under the Toxic Substances Control Act (TSCA). We conducted a systematic review of the non-cancer and cancer hazards of PDC using the EPA TSCA and Integrated Risk Information System (IRIS) frameworks. We identified 12 epidemiological, 16 toxicokinetic, 34 experimental animal, and 49 mechanistic studies. Point-of-contact respiratory effects are the most sensitive non-cancer effects after inhalation exposure, and PDC is neither a reproductive nor a developmental toxicant. PDC is not mutagenic in vivo, and while in vitro evidence is mixed, DNA strand breaks consistently occur. Nasal tumors in rats and lung tumors in mice occurred after lifetime high-level inhalation exposure. Cholangiocarcinoma (CCA) was observed in Japanese print workers exposed to high concentrations of PDC. However, co-exposures, as well as liver parasites, hepatitis, and other risk factors, may also have contributed. The cancer mode of action (MOA) analysis revealed that PDC may act through multiple biological pathways occurring sequentially and/or simultaneously, although chronic tissue damage and inflammation likely dominate. Critically, health benchmarks protective of non-cancer effects are expected to protect against cancer in humans.

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs).

For the past several decades, a relative potency approach has been used to estimate the human health risks from exposure to polycyclic aromatic hydrocarbon (PAH) mixtures. Risk estimates are derived using potency equivalence factors (PEFs; also called relative potency factors [RPFs]), based on the ratio of selected PAHs to benzo[a]pyrene (BaP), expressed qualitatively by orders of magnitude. To quantify PEFs for 18 selected carcinogenic PAHs, a systematic approach with a priori and dose response criteria was developed, building on draft work by the US EPA in 2010 and its review by US EPA Science Advisory Board (SAB) in 2011. An exhaustive search for carcinogenicity studies that included both target PAHs and BaP with environmentally relevant exposure routes found only 48 animal bioassay datasets (mostly pre-1992 based on skin painting). Only eight datasets provided adequate low-response data, and of these only four datasets were appropriate for modeling to estimate PEFs; only benzo[b]fluoranthene and cyclopenta[c,d]pyrene had a PEF that could be quantified. Thus, current knowledge of PAH carcinogenicity is insufficient to support quantitative PEFs for PAH mixtures. This highlights the long-acknowledged need for an interdisciplinary approach to estimate risks from PAH mixtures. Use of alternative and short-term toxicity testing methods, improved mixture characterization, understanding the fate and bioavailability of PAH mixtures, and understanding exposure route-related differences in carcinogenicity are discussed as ways to improve the understanding of the risks of PAHs.

Bayesian hierarchical evaluation of dose-response for peanut allergy in clinical trial screening.

Risk-based labeling based on the minimal eliciting doses (EDs) in sensitized populations is a potential replacement for precautionary allergen labeling of food allergens. We estimated the dose-response distribution for peanut allergen using data from double-blind placebo-controlled food challenges (DBPCFCs) conducted in the US at multiple sites, testing a population believed to be similar to the general U.S. food allergic population. Our final (placebo-adjusted) dataset included 548 challenges of 481 subjects. Bayesian hierarchical analysis facilitated model fitting, and accounted for variability associated with various levels of data organization. The data are best described using a complex hierarchical structure that accounts for inter-individual variability and variability across study locations or substudies. Bayesian model averaging could simultaneously consider the fit of multiple models, but the Weibull model dominated so strongly that model averaging was not needed. The ED01 and ED05 (and 95% credible intervals) are 0.052 (0.021, 0.13) and 0.49 (0.22, 0.97) mg peanut protein, respectively. Accounting for challenges with severe reactions at the LOAEL, by using the dose prior to the LOAEL as the new LOAEL, the ED01 drops to 0.029 (0.014, 0.074) mg peanut protein. Our results could aid in establishing improved food labeling guidelines in the management of food allergies.

Ethylene Oxide: Cancer Evidence Integration and Dose-Response Implications.

The International Agency for Research on Cancer (IARC) and the United States Environmental Protection Agency (USEPA) classified ethylene oxide (EtO) as a known human carcinogen. Critically, both noted that the epidemiological evidence based on lymphoid and breast cancers was "limited," but that the evidence in animal studies was "sufficient" and "extensive" (respectively) and that EtO is genotoxic. The USEPA derived one of the highest published inhalation unit risk (IUR) values (3 × 10-3 per [µg/m3 EtO]), based on results from 2 epidemiological studies. We performed focused reviews of the epidemiological and toxicological evidence on the carcinogenicity of EtO and considered the USEPA's reliance on a genotoxic mode of action to establish EtO's carcinogenicity and to determine likely dose-response patterns. Higher quality epidemiological studies demonstrated no increased risk of breast cancers or lymphohematopoietic malignancies (LHM). Similarly, toxicological studies and studies of early effect biomarkers in animals and humans provided no strong indication that EtO causes LHM or mammary cancers. Ultimately, animal data are inadequate to define the actual dose-response shape or predict tumor response at very low doses with any confidence. We conclude that the IARC and USEPA classification of EtO as a known human carcinogen overstates the underlying evidence and that the IUR derived by USEPA grossly overestimates risk.

Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol.

Background: Elevated low-density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular disease. Dietary guidance recommends reducing saturated fatty acid, trans fatty acid, and cholesterol intakes to reduce circulating LDL cholesterol. Cholesterol intake may also affect high-density lipoprotein (HDL)-cholesterol concentrations, but its impact has not been fully quantified. Objectives: The aims of this study were to investigate the dose-response relation between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol markers for cardiovascular disease risk and to provide a reference for clinicians on how changes in dietary cholesterol intake affect circulating cholesterol concentrations, after accounting for intakes of fatty acids. Methods: We used a Bayesian approach to meta-regression analysis, which uses Markov chain Monte Carlo techniques, to assess the relation between the change in dietary cholesterol (adjusted for dietary fatty acids) and changes in LDL and HDL cholesterol based on the use of data from randomized dietary intervention trials. Results: Fifty-five studies (2652 subjects) were included in the analysis. The nonlinear Michaelis-Menten (MM) and Hill models best described the data across the full spectrum of dietary cholesterol changes studied (0-1500 mg/d). Mean predicted changes in LDL cholesterol for an increase of 100 mg dietary cholesterol/d were 1.90, 4.46, and 4.58 mg/dL for the linear, nonlinear MM, and Hill models, respectively. Conclusions: The change in dietary cholesterol was positively associated with the change in LDL-cholesterol concentration. The linear and MM models indicate that the change in dietary cholesterol is modestly inversely related to the change in circulating HDL-cholesterol concentrations in men but is positively related in women. The clinical implications of HDL-cholesterol changes associated with dietary cholesterol remain uncertain.

Benchmark dose (BMD) modeling: current practice, issues, and challenges.

Benchmark dose (BMD) modeling is now the state of the science for determining the point of departure for risk assessment. Key advantages include the fact that the modeling takes account of all of the data for a particular effect from a particular experiment, increased consistency, and better accounting for statistical uncertainties. Despite these strong advantages, disagreements remain as to several specific aspects of the modeling, including differences in the recommendations of the US Environmental Protection Agency (US EPA) and the European Food Safety Authority (EFSA). Differences exist in the choice of the benchmark response (BMR) for continuous data, the use of unrestricted models, and the mathematical models used; these can lead to differences in the final BMDL. It is important to take confidence in the model into account in choosing the BMDL, rather than simply choosing the lowest value. The field is moving in the direction of model averaging, which will avoid many of the challenges of choosing a single best model when the underlying biology does not suggest one, but additional research would be useful into methods of incorporating biological considerations into the weights used in the averaging. Additional research is also needed regarding the interplay between the BMR and the UF to ensure appropriate use for studies supporting a lower BMR than default values, such as for epidemiology data. Addressing these issues will aid in harmonizing methods and moving the field of risk assessment forward.

Chemical-induced asthma and the role of clinical, toxicological, exposure and epidemiological research in regulatory and hazard characterization approaches.

Uncertainties in understanding all potential modes-of-action for asthma induction and elicitation hinders design of hazard characterization and risk assessment methods that adequately screen and protect against hazardous chemical exposures. To address this challenge and identify current research needs, the University of Cincinnati and the American Cleaning Institute hosted a webinar series to discuss the current state-of-science regarding chemical-induced asthma. The general consensus is that the available database, comprised of data collected from routine clinical and validated toxicological tests, is inadequate for predicting or determining causal relationships between exposures and asthma induction for most allergens. More research is needed to understand the mechanism of asthma induction and elicitation in the context of specific chemical exposures and exposure patterns, and the impact of population variability and patient phenotypes. Validated tools to predict respiratory sensitization and to translate irritancy assays to asthma potency are needed, in addition to diagnostic biomarkers that assess and differentiate allergy versus irritant-based asthmatic responses. Diagnostic methods that encompass the diverse etiologies of asthmatic responses and incorporate robust exposure measurements capable of capturing different temporal patterns of complex chemical mixtures are needed. In the absence of ideal tools, risk assessors apply hazard-based safety assessment methods, in conjunction with active risk management, to limit potential asthma concerns, proactively identify new concerns, and ensure deployment of approaches to mitigate asthma-related risks.

Cleaning and asthma: A systematic review and approach for effective safety assessment.

Research indicates a correlative relationship between asthma and use of consumer cleaning products. We conduct a systematic review of epidemiological literature on persons who use or are exposed to cleaning products, both in occupational and domestic settings, and risk of asthma or asthma-like symptoms to improve understanding of the causal relationship between exposure and asthma. A scoring method for assessing study reliability is presented. Although research indicates an association between asthma and the use of cleaning products, no study robustly investigates exposure to cleaning products or ingredients along with asthma risk. This limits determination of causal relationships between asthma and specific products or ingredients in chemical safety assessment. These limitations, and a lack of robust animal models for toxicological assessment of asthma, create the need for a weight-of-evidence (WoE) approach to examine an ingredient or product's asthmatic potential. This proposed WoE method organizes diverse lines of data (i.e., asthma, sensitization, and irritation information) through a systematic, hierarchical framework that provides qualitatively categorized conclusions using hazard bands to predict a specific product or ingredient's potential for asthma induction. This work provides a method for prioritizing chemicals as a first step for quantitative and scenario-specific safety assessments based on their potential for inducing asthmatic effects. Acetic acid is used as a case study to test this framework.

Derivation of an oral toxicity reference value for nickel.

Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water, soil, and air, as well as food. This paper presents an assessment of the oral nickel toxicity data in support of non-cancer health-based oral exposure limits or toxicity reference values (TRVs). This paper derives TRVs for three populations of interest: adults, toddlers, and people who have been dermally sensitized to nickel. The adult/lifetime TRV of 20 µg Ni/kg-day is based on post-implantation loss/perinatal mortality in a 2-generation reproductive study in rats. Several recent assessments by regulatory agencies have used the same study and endpoint, but the dose-response modeling conducted here was more appropriate for the study design. Toxicokinetic data from rats and humans indicate that the applied uncertainty factors are very conservative. Because the endpoint relates to fetal exposure and is not relevant to toddlers, a toddler TRV was derived based on decreased body weight in young rats; this TRV was also 20 µg Ni/kg-day. A separate TRV of 4 µg Ni/kg in addition to Ni in food was derived for protection of nickel-sensitized populations from flare-up of dermatitis, based on studies of single exposures in humans under conditions that maximize oral absorption.

Meta-regression analysis of the effect of trans fatty acids on low-density lipoprotein cholesterol.

We conducted a meta-regression of controlled clinical trial data to investigate quantitatively the relationship between dietary intake of industrial trans fatty acids (iTFA) and increased low-density lipoprotein cholesterol (LDL-C). Previous regression analyses included insufficient data to determine the nature of the dose response in the low-dose region and have nonetheless assumed a linear relationship between iTFA intake and LDL-C levels. This work contributes to the previous work by 1) including additional studies examining low-dose intake (identified using an evidence mapping procedure); 2) investigating a range of curve shapes, including both linear and nonlinear models; and 3) using Bayesian meta-regression to combine results across trials. We found that, contrary to previous assumptions, the linear model does not acceptably fit the data, while the nonlinear, S-shaped Hill model fits the data well. Based on a conservative estimate of the degree of intra-individual variability in LDL-C (0.1 mmoL/L), as an estimate of a change in LDL-C that is not adverse, a change in iTFA intake of 2.2% of energy intake (%en) (corresponding to a total iTFA intake of 2.2-2.9%en) does not cause adverse effects on LDL-C. The iTFA intake associated with this change in LDL-C is substantially higher than the average iTFA intake (0.5%en).

A tiered asthma hazard characterization and exposure assessment approach for evaluation of consumer product ingredients.

Asthma is a complex syndrome with significant consequences for those affected. The number of individuals affected is growing, although the reasons for the increase are uncertain. Ensuring the effective management of potential exposures follows from substantial evidence that exposure to some chemicals can increase the likelihood of asthma responses. We have developed a safety assessment approach tailored to the screening of asthma risks from residential consumer product ingredients as a proactive risk management tool. Several key features of the proposed approach advance the assessment resources often used for asthma issues. First, a quantitative health benchmark for asthma or related endpoints (irritation and sensitization) is provided that extends qualitative hazard classification methods. Second, a parallel structure is employed to include dose-response methods for asthma endpoints and methods for scenario specific exposure estimation. The two parallel tracks are integrated in a risk characterization step. Third, a tiered assessment structure is provided to accommodate different amounts of data for both the dose-response assessment (i.e., use of existing benchmarks, hazard banding, or the threshold of toxicological concern) and exposure estimation (i.e., use of empirical data, model estimates, or exposure categories). Tools building from traditional methods and resources have been adapted to address specific issues pertinent to asthma toxicology (e.g., mode-of-action and dose-response features) and the nature of residential consumer product use scenarios (e.g., product use patterns and exposure durations). A case study for acetic acid as used in various sentinel products and residential cleaning scenarios was developed to test the safety assessment methodology. In particular, the results were used to refine and verify relationships among tiered approaches such that each lower data tier in the approach provides a similar or greater margin of safety for a given scenario.

Human chemosensory perception of methyl isothiocyanate: chemesthesis and odor.

An unpublished laboratory study by Russell and Rush (1996) showed that human subjects sense the presence of methyl isothiocyanate (MITC) via the eyes at concentrations as low as hundreds of ppb in air, with dependence upon duration of exposure. The longer the stimulation, the lower the concentrations sensed. Application of benchmark concentration (BMC10) modeling indicated a best estimate of 330 ppb by the end of 4h. With a confidence limit (BMCL) applied, the level dropped to 220 ppb, when employing a probit model. Receptors known as TRPA1 ion channels present in trigeminal and associated peripheral afferent nerves have shown particular sensitivity to isothiocyanates. Sensitivity to these electrophiles, which occur naturally in plants (e.g., capers and mustard greens), most likely derives from a mechanism of reversible covalent bonding. Such sensing can provide warning of potential damage rather than actual damage itself. Based upon its reputation as a lachrymator, Russell and Rush assumed that the eyes would sense MITC, before the upper airways, so gathered no data from the airways, except for odor. Field results from spills and results of acute exposures to animals covered in Dourson et al. (2010) add pertinent information on the matter.

Dose response assessment for effects of acute exposure to methyl isothiocyanate (MITC).

The preplant fumigants, metam-sodium, metam-potassium, and dazomet undergo decomposition to the biocide methyl isothiocyanate (MITC) in moist soils. Since MITC vapor can migrate from its site of application, we developed an estimate of health protective concentrations for airborne exposures to MITC that prevents effects among bystanders near treated agricultural fields. Our findings show that, at concentrations of environmental relevance, MITC most likely acts via stimulation of the trigeminal nerve, which mediates sensory irritation in the eyes and nose. Several lines of evidence support the conclusion that sensory irritation of the eyes is the most sensitive effect relevant for health risk assessment arising from short-term MITC exposures. The outcome of a clinical study that included sensitive individuals and measured multiple ocular responses to irritation (e.g., perceived irritation, tearing, and blinking of the eyes) is consistent with this proposed mode of action, as are experimental animal data. Databases and studies by the California Department of Pesticide Regulation (CDPR) show that, in accidental exposures, human eye irritation is consistently the most sensitive endpoint at low-modeled acute exposure and is often the most sensitive endpoint from acute exposures of unknown, but likely higher, concentrations. Based upon benchmark concentration lower limits from the clinical study and consideration of uncertainties, health protective concentrations of MITC were estimated as 0.2 ppm for 4h of exposure and 0.8 ppm for 14-min of exposure.