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In 2016, the American Conference of Governmental Industrial Hygienists (ACGIH) lowered the 8-hr Threshold Limit Value - time-weighted average (TLV-TWA) for toluene diisocyanate (TDI) from 5 ppb to 1 ppb, and the 15-min short-term exposure limit (STEL) from 20 ppb to 5 ppb. We evaluated ACGIH's basis for lowering these values. It is our opinion that the ACGIH's evaluation of the evidence for occupational asthma and respiratory effects from TDI exposure does not fully integrate the results of all the available human and animal studies. We found that some studies reported occupational asthma cases at TWAs less than 5 ppb, but these cases were likely caused by peak exposures above 20 ppb. Advances in industrial hygiene have reduced peak exposures and the incidence of upset conditions, such as spills and accidents, in modern TDI facilities. Taken together, the human evidence indicates that adherence to the previous 8-hr TLV-TWA and 15-min STEL (5 ppb and 20 ppb, respectively) prevents most, if not all, cases of occupational asthma, and eliminates or reduces the risk of lung function decrements and other respiratory effects. While limited, the animal literature supports the human evidence and indicates that TDI-induced asthma is a threshold phenomenon. We conclude that ACGIH's decision to lower the TLV-TWA and STEL values for TDI is not adequately supported.

Human exposure to toluene diisocyanate (TDI) occurs mainly through inhalation of vapors in occupational settings where TDI is produced or used, but dermal exposure to TDI is also possible during some operations. Because of a recent epidemiology study reporting a possible association with lung cancer risk in workers with potential dermal exposure to TDI, we evaluated the evidence from epidemiological, toxicological, and toxicokinetic studies to assess whether it is likely that dermal exposure to TDI can cause human respiratory cancers. We found that the reported associations with respiratory cancers in the epidemiology studies do not support TDI as a causal factor, as there are other explanations that are more likely than causation, such as confounding by smoking and low socioeconomic status. Experimental animal and genotoxicity studies indicate that the carcinogenic potential of TDI depends on its conversion to toluene diamine (TDA), and there is no evidence of systemic availability of TDA after dermal or inhalation exposure to TDI. Also, systemic uptake of TDI is very low after dermal exposure, and any absorbed TDI is more likely to react with biomolecules on or below the skin surface than to form TDA. Even if some TDA formation occurred after dermal exposure to TDI, TDA does not induce respiratory tract tumors in experimental animals after either dermal or oral exposure. We conclude that the available evidence indicates that dermal TDI exposure does not cause respiratory cancers in humans. Keywords: Carcinogenicity, Dermal exposure, Diisocyanates, Polyurethane foam, Respiratory cancer, Toluene diisocyanate

To determine whether evidence indicates that short-term exposure to ambient concentrations of ozone in the United States can affect asthma severity, we systematically reviewed published controlled human exposure, epidemiology, and animal toxicity studies. The strongest evidence for a potential causal relationship came from epidemiology studies reporting increased emergency department visits and hospital admissions for asthma following elevated ambient ozone concentrations. However, while controlled exposure studies reported lung function decrements and increased asthma symptoms following high ozone exposures 160-400 parts per billion [ppb]), epidemiology studies evaluating similar outcomes reported less consistent results. Animal studies showed changes in pulmonary function at high ozone concentrations (> 500ppb), although there is substantial uncertainty regarding the relevance of these animal models to human asthma. Taken together, the weight of evidence indicates that there is at least an equal likelihood that either explanation is true, i.e., the strength of the evidence for a causal relationship between short-term exposure to ambient ozone concentrations and asthma severity is "equipoise and above."

There is a relatively large body of research on the potential cardiovascular (CV) effects associated with short-term ozone exposure (defined by EPA as less than 30 days in duration). We conducted a weight-of-evidence (WoE) analysis to assess whether it supports a causal relationship using a novel WoE framework adapted from the US EPA's National Ambient Air Quality Standards causality framework. Specifically, we synthesized and critically evaluated the relevant epidemiology, controlled human exposure, and experimental animal data and made a causal determination using the same categories proposed by the Institute of Medicine report Improving the Presumptive Disability Decision-making Process for Veterans ( IOM 2008). We found that the totality of the data indicates that the results for CV effects are largely null across human and experimental animal studies. The few statistically significant associations reported in epidemiology studies of CV morbidity and mortality are very small in magnitude and likely attributable to confounding, bias, or chance. In experimental animal studies, the reported statistically significant effects at high exposures are not observed at lower exposures and thus not likely relevant to current ambient ozone exposures in humans. The available data also do not support a biologically plausible mechanism for CV effects of ozone. Overall, the current WoE provides no convincing case for a causal relationship between short-term exposure to ambient ozone and adverse effects on the CV system in humans, but the limitations of the available studies preclude definitive conclusions regarding a lack of causation. Thus, we categorize the strength of evidence for a causal relationship between short-term exposure to ozone and CV effects as "below equipoise."

The National Academy of Sciences (NAS) Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde proposed a "roadmap" for reform and improvement of the Agency's risk assessment process. Specifically, it called for development of a transparent and defensible methodology for weight-of-evidence (WoE) assessments. To facilitate development of an improved process, we developed a white paper that reviewed approximately 50 existing WoE frameworks, seeking insights from their variations and nominating best practices for WoE analyses of causation of chemical risks. Four phases of WoE analysis were identified and evaluated in each framework: (1) defining the causal question and developing criteria for study selection, (2) developing and applying criteria for review of individual studies, (3) evaluating and integrating evidence and (4) drawing conclusions based on inferences. We circulated the draft white paper to stakeholders and then held a facilitated, multi-disciplinary invited stakeholder workshop to broaden and deepen the discussion on methods, rationales, utility and limitations among the surveyed WoE frameworks. The workshop developed recommendations for improving the conduct of WoE evaluations. Based on the analysis of the 50 frameworks and discussions at the workshop, best practices in conducting WoE analyses were identified for each of the four phases. Many of these best practices noted from the analysis and workshop could be implemented immediately, while others may require additional refinement as part of the ongoing discussions for improving the scientific basis of chemical risk assessments.

Exposure to elevated levels of ozone has been associated with a variety of respiratory-related health endpoints in both epidemiology and controlled human exposure studies, including lung function decrements and airway inflammation. A mode of action (MoA) for these effects has not been established, but it has been proposed that they may occur through ozone-induced activation of neural reflexes. We critically reviewed experimental studies of ozone exposure and neural reflex activation and applied the International Programme on Chemical Safety (IPCS) mode-of-action/human relevance framework to evaluate the biological plausibility and human relevance of this proposed MoA. Based on the currently available experimental data, we found that the proposed MoA of neural reflex activation is biologically plausible for the endpoint of ozone-induced lung function decrements at high ozone exposures, but further studies are needed to fill important data gaps regarding the relevance of this MoA at lower exposures. A role for the proposed MoA in ozone-induced airway inflammation is less plausible, as the evidence is conflicting and is also of unclear relevance given the lack of studies conducted at lower exposures. The evidence suggests a different MoA for ozone-induced inflammation that may still be linked to the key events in the proposed MoA, such that neural reflex activation may have some degree of involvement in modulating ozone-induced neutrophil influx, even if it is not a direct role.

Recent scientific debate has focused on the potential for exposure to methanol to cause lymphomas in humans. The concern stems from a few animal studies reporting an association, although evidence suggests the studies may have been confounded by chronic respiratory infection. Although the toxicological evidence for methanol carcinogenesis is weak, two modes of action have been put forth, one involving metabolism of methanol to formaldehyde, followed by formaldehyde induction of lymphoma, and another involving oxidative stress caused by hydrogen peroxide release during catalase-induced metabolism of methanol to formaldehyde. In this article, we apply our Hypothesis-Based Weight-of-Evidence (HBWoE) approach to evaluate the evidence regarding methanol exposure and lymphoma, attending to how human, animal, and mode-of-action results inform one another, tracing the logic of inference within and across all studies, and articulating how one could account for the suite of available observations. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the apparent association between methanol exposure and lymphoma in some animal studies is weak and strains biological plausibility, and is better interpreted as due to confounding or to a mechanism not relevant in humans.

The inhalation of nickel-containing dust has been associated with an increased risk of respiratory cancer in workplaces that process and refine sulfidic nickel mattes, where workers are exposed to mixtures of sulfidic, oxidic, water-soluble, and metallic forms of nickel. Because there is great complexity in the physical and chemical properties of nickel species, it is of interest which specific nickel forms are associated with carcinogenic risk. A bioavailability model for tumor induction by nickel has been proposed, based on the results of animal inhalation bioassays conducted on four nickel-containing substances. The nickel ion bioavailability model holds that a nickel-containing substance must release nickel ions that become bioavailable at the nucleus of epithelial respiratory cells for the substance to be carcinogenic, and that the carcinogenic potency of the substance is proportional to the degree to which the nickel ions are bioavailable at that site. This hypothesis updates the nickel ion theory, which holds that exposure to any nickel-containing substance leads to an increased cancer risk. The bioavailability of nickel ions from nickel-containing substances depends on their respiratory toxicity, clearance, intracellular uptake, and both extracellular and intracellular dissolution. Although some data gaps were identified, a weight-of-evidence evaluation indicates that the nickel ion bioavailability model may explain the existing animal and in vitro data better than the nickel ion theory. Epidemiological data are not sufficiently robust for determining which model is most appropriate, but are consistent with the nickel ion bioavailability model. Information on nickel bioavailability should be incorporated into future risk assessments.

It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including alpha-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16(INK4a) (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated.

The US Environmental Protection Agency (EPA) recently concluded that there is likely to be a causal relationship between short-term (< 30 days) ozone exposure and cardiovascular (CV) effects; however, biological mechanisms to link transient effects with chronic cardiovascular disease (CVD) have not been established. Some studies assessed changes in circulating levels of biomarkers associated with inflammation, oxidative stress, coagulation, vasoreactivity, lipidology, and glucose metabolism after ozone exposure to elucidate a biological mechanism. We conducted a weight-of-evidence (WoE) analysis to determine if there is evidence supporting an association between changes in these biomarkers and short-term ozone exposure that would indicate a biological mechanism for CVD below the ozone National Ambient Air Quality Standard (NAAQS) of 75 parts per billion (ppb). Epidemiology findings were mixed for all biomarker categories, with only a few studies reporting statistically significant changes and with no consistency in the direction of the reported effects. Controlled human exposure studies of 2 to 5 hours conducted at ozone concentrations above 75 ppb reported small elevations in biomarkers for inflammation and oxidative stress that were of uncertain clinical relevance. Experimental animal studies reported more consistent results among certain biomarkers, although these were also conducted at ozone exposures well above 75 ppb and provided limited information on ozone exposure-response relationships. Overall, the current WoE does not provide a convincing case for a causal relationship between short-term ozone exposure below the NAAQS and adverse changes in levels of biomarkers within and across categories, but, because of study limitations, they cannot not provide definitive evidence of a lack of causation.

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer–prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. Cancer Res; 76(5); 1055–65. ©2015 AACR.

The vision of the NAS Committee represents a transition in toxicology from an emphasis on the study of apical endpoints in whole animals to a focus on the study of pathway perturbations, based primarily on in vitro data, from which dose-response models will ultimately be developed. It should be emphasized that this vision does not seek to eliminate whole-animal testing altogether; however, it does aim to eventually use animal testing to a far less extent than in our current system. Such a change to the current method of toxicity testing represents an important goal for many reasons. For example, toxicity testing needs to incorporate the knowledge that has been developed through the most recent advances in research, particularly at the molecular level. Through the application of mechanistic information resulting from the testing of chemicals by the proposed in vitro methods, it may be possible to predict the toxicity of similar chemicals that have not yet been tested in whole animals. The number of chemicals in commercial use for which we have adequate toxicity information is limited, and higherthroughput assays have the potential to increase this number. While the vision’s approach would result in a loss of information from a reduction in testing at high doses, the NAS Committee has proposed that this lack of information would be compensated by a greater understanding of effects at low doses, and that such an understanding can eventually be applied in a practical context. Clearly, however, there are multiple challenges to the actual implementation of the vision. First, we need to consider the vast biological complexity of whole organisms. Will in vitro assays for pathway perturbations, in the absence of some understanding from in vivo studies, be able to identify all of the possible toxic endpoints of a particular chemical? The application of in vitro methods may be a slow and uncertain process without some initial hypotheses about likely critical apical endpoints for a particular chemical. In contrast, with animal bioassays, we can identify toxic endpoints that we may not have originally thought to look for, through the analysis of different target organs. An understanding of how pathway activation and the corresponding dose-response relationships change with differences in the duration of exposure will be necessary, and yet it may be difficult to distinguish between acute, subchronic, and chronic effects at the pathway level. In addition, in vitro assays cannot mirror the metabolism of a whole animal, and the NAS Committee has agreed that much research will be needed to ensure that the new testing methods associated with their vision fully evaluate the effects of both chemicals and their metabolites. The development of ‘-omic’ technologies (such as genomics, proteomics, and metabolomics) is a key element for advancing the vision of the NAS Committee; however, there are challenges to the use of these approaches for the prediction of in vivo toxicity. Rhomberg et al. state that

We used a hypothesis-based weight-of-evidence (HBWoE) approach to analyze the evidence regarding the hypothesis that chlorpyrifos can cause neurodevelopmental effects below the threshold for inhibition of acetylcholinesterase activity in the nervous system, which is an established mode of action for chlorpyrifos neurotoxicity. The epidemiology data do not consistently demonstrate associations between chlorpyrifos exposure and neurodevelopmental toxicity, and the animal toxicity data do not provide clear evidence that neurodevelopmental effects occur at doses below the threshold for acetylcholinesterase inhibition. The alternative mechanisms proposed to underlie potential neurodevelopmental effects in humans have been observed in the absence of acetylcholinesterase inhibition in a few in vitro studies but not in the developing brain in vivo. We provide perspective on the HBWoE approach compared with frameworks developed by the United States Environmental Protection Agency and the European Center for Ecotoxicology and Toxicology of Chemicals. We suggest that our HBWoE approach offers advantages over these frameworks in providing a better perspective on how to integrate all of the relevant data and how to use each line of evidence to inform the integration of other kinds of data or compare alternative hypotheses. Based on an HBWoE analysis, we conclude that a causal association between chlorpyrifos exposure and neurodevelopmental effects in the absence of acetylcholinesterase inhibition in the brain is not plausible in humans, and the few positive associations observed in epidemiology studies are most likely attributable to alternative explanations.

IARC is reassessing the human carcinogenicity of nickel compounds in 2009. To address the inconsistencies among results from studies of water-soluble nickel compounds, we conducted a weight-of-evidence analysis of the relevant epidemiological, toxicological, and carcinogenic mode-of-action data. We found the epidemiological evidence to be limited, in that some, but not all, data suggest that exposure to soluble nickel compounds leads to increased cancer risk in the presence of certain forms of insoluble nickel. Although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is limited evidence that suggests it may act as a tumor promoter. The mode-of-action data suggest that soluble nickel compounds will not be able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ions to nuclear sites of target cells. Although the mode-of-action data suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. The mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all. The weight of evidence does not indicate that soluble nickel compounds are complete carcinogens, and there is only limited evidence that they could act as tumor promoters.

Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (por= 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p(interaction)0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E(2) induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival.