Recommendations for further revisions to improve the International Agency for Research on Cancer (IARC) Monograph program.

In 2019, the International Agency for Research on Cancer (IARC) "Preamble to the IARC Monographs" expanded guidance regarding the scientific approaches that should be employed in its monographs. These amendments to the monograph development process are an improvement but still fall short in several areas. While the revised Preamble lays out broad methods and approaches to evaluate scientific evidence, there is a lack of specificity with regard to how IARC Working Groups will conduct consistent evaluations in a standardized, objective, and transparent manner; document systematic review and evidence integration actions, and substantiate how these actions and decisions inform the ultimate classifications. Furthermore, no guidance is provided to ensure Working Groups consistently incorporate mechanistic evidence in a robust manner using a defined approach in the context of 21st century knowledge of modes of action. Nor are the conclusions of the working groups subjected to outside, independent scientific peer review. Continued improvements and modernization of the procedures for evaluating, presenting, and communicating study quality, and in the methods used to conduct and peer-review evidence-based decision making will benefit the Working Group members, the IARC Monographs Programme overall, and the international regulatory community and public who rely upon the monographs.

Improving risk assessment approaches for chemicals with both endogenous and exogenous exposures.

To conduct risk assessments of exogenous chemicals for which there are also endogenous exposures, knowledge of the chemistry and biology of both types of exposures needs to be integrated into problem formulation and carried through to risk characterization. This issue is framed in a risk assessment context, highlighting the importance of quantifying increments of dose from all sources of the same or similar chemicals interacting with biological targets; understanding the influence of endogenous chemical concentrations on disease risk; and assessing total dose to targets in evaluating risk from incremental environmental exposures. Examples of recent assessments illustrate the importance of addressing this issue. Evaluations of data on blood or organ concentrations of ammonia, methanol, formaldehyde, acetaldehyde, and three gaseous signaling molecules (hydrogen sulfide, carbon monoxide, and nitric oxide) provide examples where current data are already informing perspectives on relative exposures at the portal of entry and systemically. To facilitate quality risk assessments of exogenous chemicals with endogenous exposures, a series of specific questions are presented that need to be addressed in systematic review to enhance problem formulation, improve the development of holistic conceptual models, and to facilitate the identification of priority data needs for improving risk assessments.

Health- and vegetative-based effect screening values for ethylene.

Ethylene (ET) is ubiquitous in the environment and is produced both naturally and due to anthropogenic sources. Interestingly, the majority of ambient ET contribution is from natural sources and anthropogenic sources contribute only a minor portion. While microbes and plants naturally produce a large amount of ET, mammals are reported to produce only a small amount of ET endogenously. Anthropogenic sources of ET include the combustion of gas, fuel, coal and biomass. ET is also widely used as an intermediate to make other chemicals and products and is also used for controlled ripening of fruits and vegetables. Although, a review of human and laboratory animal studies indicate ET to be relatively non-toxic, there is concern about the potential toxicity of ET because ET is metabolically converted to ethylene oxide (EtO). EtO has been classified to be carcinogenic to human by the inhalation route by the International Agency for Research on Cancer (IARC) cancer. ET, however, has been classified as a Group 3 chemical which indicates it is not classified as a human carcinogen by IARC. Several studies have reported ET to cause adverse effects to plant species (vegetation effects) at concentrations that are not adverse to humans. Therefore, the Texas Commission of Environmental Quality (TCEQ) conducted detailed health and welfare (odor and vegetation) based assessments of ET to develop both health and vegetative based toxicity factors in 2008 in accordance with TCEQ guidelines. The health assessment based on well-conducted animal toxicity studies resulted in identification of higher points of departures and subsequently higher effect screening levels (ESLs) that were more than a magnitude higher than the threshold adverse effect level for vegetative effects for ET. Further, based on a weight-of-evidence evaluation of potential mutagenic and carcinogenic mode-of-actions for ET it appears the metabolic conversion of ET to EtO is of insufficient magnitude to cause concern of potential cancer risk. Therefore, the short-term ESL for air permit reviews and air monitoring evaluations is the vegetation-based ESL of 1200 ppb as it is more than a magnitude lower than the health-based acute ESL of 150,000 ppb. Similar to the acute derivation, the chronic evaluation resulted in the derivation of a chronic vegetation based ESL of 30 ppb that was much lower than the chronic ESL of 1600 ppb. In summary, the TCEQ's acute and chronic ESLs for vegetation will protect the general public from short-term and long-term adverse health and welfare effects. The general public includes children, the elderly, pregnant women, and people with pre-existing health conditions.

An updated inhalation unit risk factor for arsenic and inorganic arsenic compounds based on a combined analysis of epidemiology studies.

The United States Environmental Protection Agency (USEPA) developed an inhalation unit risk factor (URF) of 4.3E-03 per µg/m(3) for arsenic in 1984 for excess lung cancer mortality based on epidemiological studies of workers at two smelters: the Asarco smelter in Tacoma, Washington and the Anaconda smelter in Montana. Since the USEPA assessment, new studies have been published and exposure estimates were updated at the Asarco and Anaconda smelters and additional years of follow-up evaluated. The Texas Commission on Environmental Quality (TCEQ) has developed an inhalation URF for lung cancer mortality from exposures to arsenic and inorganic arsenic compounds based on a newer epidemiology study of Swedish workers and the updates of the Asarco and Anaconda epidemiology studies. Using a combined analysis approach, the TCEQ weighted the individual URFs from these three epidemiology cohort studies, to calculate a final inhalation URF of 1.5E-04 per µg/m(3). In addition, the TCEQ also conducted a sensitivity analysis, in which they calculated a URF based on a type of meta-analysis, and these results compared well with the results of the combined analysis. The no significant concentration level (i.e., air concentration at 1 in 100,000 excess lung cancer mortality) is 0.067µg/m(3). This value will be used to evaluate ambient air monitoring data so the general public in Texas is protected against adverse health effects from chronic exposure to arsenic.

Evaluation of acute inhalation toxicity for chemicals with limited toxicity information.

A large reference database consisting of acute inhalation no-observed-adverse-effect levels (NOAELs) and acute lethality data for 97 chemicals was compiled to investigate two methods to derive health-protective concentrations for chemicals with limited toxicity data for the evaluation of one-hour intermittent inhalation exposure. One method is to determine threshold of concern (TOC) concentrations for acute toxicity potency categories and the other is to determine NOAEL-to-LC(50) ratios. In the TOC approach, 97 chemicals were classified based on the Globally Harmonized System of Classification and Labeling of Chemicals proposed by the United Nations into different acute toxicity categories (from most toxic to least toxic): Category 1, Category 2, Category 3, Category 4, and Category 5. The tenth percentile of the cumulative percentage distribution of NOAELs in each category was determined and divided by an uncertainty factor of 100 to derive the following health-protective TOC concentrations: 4microg/m(3) for chemicals classified in Category 1; 20microg/m(3) for Category 2; 125microg/m(3) for both Categories 3 and 4; and 1000microg/m(3) for Category 5. For the NOAEL-to-LC(50) ratio approach, 55 chemicals with NOAEL exposure durations < or = 24 hour were used to calculate NOAEL-to-LC(50) ratios. The tenth percentile of the cumulative percentage distribution of the ratios was calculated and divided by an uncertainty factor of 100 to produce a composite factor equal to 8.3x10(-5). For a chemical with limited toxicity information, this composite factor is multiplied by a 4-hour LC(50) value or other appropriate acute lethality data. Both approaches can be used to produce an estimate of a conservative threshold air concentration below which no appreciable risk to the general population would be expected to occur after a one-hour intermittent exposure.