International Agency For Research On Cancer Monographs Research Articles

Ten years of using key characteristics of human carcinogens to organize and evaluate mechanistic evidence in IARC Monographs on the identification of carcinogenic hazards to humans: Patterns and associations.

Systematic review and evaluation of mechanistic evidence using the Key Characteristics approach was proposed by the International Agency for Research on Cancer (IARC) in 2012 and used by the IARC Monographs Working Groups since 2015. Key Characteristics are 10 features of agents known to cause cancer in humans. From 2015 to 2022, a total of 19 Monographs (73 agents combined) used Key Characteristics for cancer hazard classification. We hypothesized that a retrospective analysis of applications of the Key Characteristics approach to cancer hazard classification using heterogenous mechanistic data on diverse agents would be informative for systematic reviews in decision-making. We extracted information on the conclusions, data types, and the role mechanistic data played in the cancer hazard classification from each Monograph. Statistical analyses identified patterns in the use of Key Characteristics, as well as trends and correlations among Key Characteristics, data types, and ultimate decisions. Despite gaps in data for many agents and Key Characteristics, several significant results emerged. Mechanistic data from in vivo animal, in vitro animal, and in vitro human studies were most impactful in concluding that an agent could cause cancer via a Key Characteristic. To exclude the involvement of a Key Characteristic, data from large-scale systematic in vitro testing programs such as ToxCast, were most informative. Overall, increased availability of systemized data streams, such as human in vitro data, would provide the basis for more confident and informed conclusions about both positive and negative associations and inform expert judgments on cancer hazard.

The effect of occupational exposure to welding fumes on trachea, bronchus and lung cancer: A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury

BackgroundThe World Health Organization (WHO) and the International Labour Organization (ILO) are the producers of the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury (WHO/ILO Joint Estimates). Welding fumes have been classified as carcinogenic to humans (Group 1) by the WHO International Agency for Research on Cancer (IARC) in IARC Monograph 118; this assessment found sufficient evidence from studies in humans that welding fumes are a cause of lung cancer. In this article, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from trachea, bronchus, and lung cancer attributable to occupational exposure to welding fumes, to inform the development of WHO/ILO Joint Estimates on this burden of disease (if considered feasible). ObjectivesWe aimed to systematically review and meta-analyse estimates of the effect of any (or high) occupational exposure to welding fumes, compared with no (or low) occupational exposure to welding fumes, on trachea, bronchus, and lung cancer (three outcomes: prevalence, incidence, and mortality). Data sourcesWe developed and published a protocol, applying the Navigation Guide as an organizing systematic review framework where feasible. We searched electronic databases for potentially relevant records from published and unpublished studies, including Medline, EMBASE, Web of Science, CENTRAL and CISDOC. We also searched grey literature databases, Internet search engines, and organizational websites; hand-searched reference lists of previous systematic reviews; and consulted additional experts. Study eligibility and criteriaWe included working-age (≥15 years) workers in the formal and informal economy in any Member State of WHO and/or ILO but excluded children (<15 years) and unpaid domestic workers. We included randomized controlled trials, cohort studies, case-control studies, and other non-randomized intervention studies with an estimate of the effect of any (or high) occupational exposure to welding fumes, compared with occupational exposure to no (or low) welding fumes, on trachea, bronchus, and lung cancer (prevalence, incidence, and mortality). Study appraisal and synthesis methodsAt least two review authors independently screened titles and abstracts against the eligibility criteria at a first review stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. If studies reported odds ratios, these were converted to risk ratios (RRs). We combined all RRs using random-effects meta-analysis. Two or more review authors assessed the risk of bias, quality of evidence, and strength of evidence, using the Navigation Guide tools and approaches adapted to this project. Subgroup (e.g., by WHO region and sex) and sensitivity analyses (e.g., studies judged to be of “high”/“probably high” risk of bias compared with “low”/“probably low” risk of bias) were conducted. ResultsForty-one records from 40 studies (29 case control studies and 11 cohort studies) met the inclusion criteria, comprising over 1,265,512 participants (≥22,761 females) in 21 countries in three WHO regions (Region of the Americas, European Region, and Western Pacific Region). The exposure and outcome were generally assessed by job title or self-report, and medical or administrative records, respectively. Across included studies, risk of bias was overall generally probably low/low, with risk judged high or probably high for several studies in the domains for misclassification bias and confounding.Our search identified no evidence on the outcome of having trachea, bronchus, and lung cancer (prevalence). Compared with no (or low) occupational exposure to welding fumes, any (or high) occupational exposure to welding fumes increased the risk of acquiring trachea, bronchus, and lung cancer (incidence) by an estimated 48 % (RR 1.48, 95 % confidence interval [CI] 1.29–1.70, 23 studies, 57,931 participants, I2 24 %; moderate quality of evidence). Compared with no (or low) occupational exposure to welding fumes, any (or high) occupational exposure to welding fumes increased the risk dying from trachea, bronchus, and lung cancer (mortality) by an estimated 27 % (RR 1.27, 95 % CI 1.04–1.56, 3 studies, 8,686 participants, I2 0 %; low quality of evidence). Our subgroup analyses found no evidence for difference by WHO region and sex. Sensitivity analyses supported the main analyses. ConclusionsOverall, for incidence and mortality of trachea, bronchus, and lung cancer, we judged the existing body of evidence for human data as “sufficient evidence of harmfulness” and “limited evidence of harmfulness”, respectively. Occupational exposure to welding fumes increased the risk of acquiring and dying from trachea, bronchus, and lung cancer. Producing estimates for the burden of trachea, bronchus, and lung cancer attributable to any (or high) occupational exposure to welding fumes appears evidence-based, and the pooled effect estimates presented in this systematic review could be used as input data for the WHO/ILO Joint Estimates. Protocol identifierhttps://doi.org/10.1016/j.envint.2020.106089.

Carcinogenicity of 1,1,1-trichloroethane and four other industrial chemicals.

In October, 2021, a Working Group of 20 scientists from 12 countries met remotely at the invitation of the International Agency for Research on Cancer (IARC) to finalise their evaluation of the carcinogenicity of five agents: 1,1,1-trichloroethane, 1,2-diphenylhydrazine, diphenylamine, N-methylolacrylamide, and isophorone. These assessments will be published in Volume 130 of the IARC Monographs.1

Arsenic Biotransformation: It is a complex process

Arsenic Biotransformation: It is a complex process

LUNG CANCER ASSOCIATED WITH CARBON BLACK EXPOSURE ON BRICK WORKERS

ABSTRACTCarbon black aerosol has potential risks to human health. It has been acknowledged to cause cardiovascular and respiratory diseases in humans. International Agency for Research on Cancer (IARC) 2010 stated that carbon black classification is 2b, which is carcinogenic. This research explains a case of lung cancer due to carbon black exposure and reviews the literature of occupational cases to get the answers about the effects of carbon black exposure and the increasing risk of lung cancer for workers exposed to carbon black. The literature review was performed to answer the clinical question via electronic databases: PubMed and Google Scholar. The keywords used were ‘carbon black’ and ‘lung cancer’ and 'workers'. The inclusion criteria of this searching strategy were the workers which exposed to carbon black, meta-analysis, randomized controlled trial, systematic reviews, cohort. The exclusion criteria of this article were inaccessible articles, RCTs that have been used in the recent systematic reviews. The selected articles were then critically appraised using relevant criteria by the Oxford Center for Evidence-based Medicine. This study reviews the literature by Rota Matteo; The epidemiological evidence on the polyaromatic hydrocarbon (PAH) high exposed, perspective cohort study by Delli LD, and the control case study by Marie EPt. All the researches above showed that carbon black carcinogenic potential is the same as the IARC monograph statement that the epidemiological studies of carbon black provide possible carcinogenicity (Group of 2B). Keywords: carbon black, lung cancer, workers

Does and duration of exposure time dependent regulation of proteins in the urinary bladder of hamsters exposed to sodium arsenite

Does and duration of exposure time dependent regulation of proteins in the urinary bladder of hamsters exposed to sodium arsenite

Regulation of transgelin and GST-pi proteins in the tissues of hamsters exposed to sodium arsenite

Regulation of transgelin and GST-pi proteins in the tissues of hamsters exposed to sodium arsenite

The Monographs Programme of the International Agency for Research on Cancer. A brief history of its Preamble.

Since the early 1970s, the Monographs published by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards. The Preamble to the IARC Monographs describes the objective and scope of the Monographs Programme, the scientific principles and procedures used in developing a Monograph, the types of evidence considered, and the scientific criteria that guide the evaluations. This article presents an overview of the historical development of the Preamble from the time it began to take shape in the late 1970s up to and including the most recent update in 2019. Over the years, the IARC Monographs Programme has taken account of scientific and procedural advances in identifying, reviewing, evaluating, and integrating evidence to define causes of human cancer. Since the previous edition of the Preamble in 2006, the new developments include a stronger emphasis on mechanistic evidence based on key characteristics of carcinogens; greater consideration of exposure assessment methods in epidemiological studies; and integration of the streams of evidence on cancer in humans, cancer in experimental animals, and mechanisms in reaching the overall evaluations. Thus, the Preamble now allows an evaluation process in the absence of data from animal studies, and the evidence on key characteristics of cancer may be contributed by new approach methodologies, thus potentially reducing or avoiding the use of experimental animals.

Association between Smokeless Tobacco and risk of malignant and premalignant conditions of oral cavity: A systematic review of Indian literature.

Causative linkages of tobacco use with oral potentially malignant disorders and cancers of oral cavity have been studied. Oral squamous cell carcinoma is one of the most common cancers in India. The International Agency for Research on Cancer (IARC) monograph found a significant association between smokeless tobacco (SLT) use and oral cancer. However, only a few limited studies have been represented on the IARC monograph. Published meta-analyses have provided pooled risk estimates for oral cancers caused by tobacco, both on global and regional levels. This systematic review was aimed at summarizing all the available studies exclusively in India by collecting data from PubMed and Medline. Emphasis was laid on cohort and case–control studies, and a few cross-sectional studies for premalignant lesions were also discussed. A significant association was noticed on SLT and premalignant and malignant oral cavity lesions.

Effects of dietary fumonisins on nutrients digestibility in weanling pigs

Submitted 2020-06-15 | Accepted 2020-07-01 | Available 2020-12-01 https://doi.org/10.15414/afz.2020.23.mi-fpap.23-28 The aim of the study was to ascertain the potential effects of fumonisins on nutrients’ digestibility in the gastrointestinal tract. Eighteen (n= 6 x 3) weanling pigs from the age of 35 days were administered 0, 15 or 30 mg/kg dietary fumonisins (FB1, FB2 and FB3) for a period of 21days, after an acclimatization period of 14 days. Titanium dioxide (0.5%) was added as indigestible marker to the feed and representative fecal samples were taken during a 5-day collection period in order to determine the digestibility of crude protein, crude fat, crude fiber, starch, ash, calcium, phosphorus and energy. The final body weights, cumulative feed intake and relative organ weights of all groups were were not influenced by treatment (p&gt;0.05). Digestibility of energy, crude fiber, ash, calcium and phosphorus were significantly higher (p&lt;0.05) in the control group relative to either 15 or 30 mg/kg treated pigs. These findings suggest that fumonisins in a dose of 15 or 30 mg/kg potentially distorts total tract nutrient digestibility in weanling pigs and thus, compromise the nutritive value of the mixed feed. Keywords: fumonisins, pigs, gastrointestinal tract, nutrients digestibility References Association of Official Analytical Chemists. (2000). AOAC International, Gaithersburg, 17. ed MD, USA. Bartók, T. et al. (2010). Detection and characterization of twenty-eight isomers of fumonisin B1 (FB1) mycotoxin in a solid rice culture infected with Fusarium verticillioides by reversed-phase high-performance liquid chromatography/electrospray ionization time-of-flight and ion trap mass spectrometry. Rapid Communications in Mass Spectrometry, 24(1), 35–42. Bouhet, S. and Oswald, I.P. (2007). The intestine as a possible target for fumonisin toxicity. Molecular Nutrition and Food Research, 51(8), 925–931. Choct M. (2009). Managing gut health through nutrition. British Poultry Science, 50(1), 9–15. Ewing, W.N. (2008). The Living Gut. 2. ed. Nottingham, UK: Nottingham University Press. Gbore, F.A., Yinusa, R.I. and Salleh, B. (2010). Evaluation of sub-chronic dietary fumonisin B1 on nutrient digestibility and growth performance of rats. African Journal of Biotechnology, 9(38), 6442–6447. Gbore, F.A. (2007). Effect of dietary fumonisin B1 on histomorphology and histopathology of organs of pubertal boars. American-Eurasian Journal of Scientific Research, 2, 75–79. Gbore, F.A. and Egbunike, G.N. (2007). Influence of dietary fumonisin B1 on nutrient utilization by growing pigs. Livestock Research for Rural Development, Volume19, Article #93. Retrieved June 5, 2020 from http://www.lrrd.org/lrrd19/7/gbor19093.htm Gelineau-van Waes, J. et al. (2009). Maternal fumonisin exposure as a risk factor for neural tube defects. Advances in Food and Nutrition Research, 56, 145–181. Grenier, B. and Applegate, T. (2013). Modulation of intestinal functions following mycotoxin ingestion: Meta-analysis of published experiments in animals. Toxins, 5(2), 396–430. Harrison, L.R. et al. (1990). Pulmonary edema and hydrothorax in swine produced by fumonisin B1, a toxic metabolite of Fusarium moniliforme. Journal of Veterinary Diagnostic Investigation, 2(3), 217–221. International Agency for Research on Cancer (IARC) (2002). Working group on the evaluation of carcinogenic risks to humans. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monographs on the evaluation of carcinogenic risks to humans, 82, 1–556. Islami, F. et al. (2009). Oesophageal cancer in Golestan Province, a high-incidence area in northern Iran - a review. European Journal of Cancer, 45(18), 3156–3165. Merrill, A. H. et al. (2001). Sphingolipid metabolism: roles in signal transduction and disruption by fumonisins. Environmental Health Perspectives, 109(2), 283–289. Nelson, P.E., Desjardins, A.E. and Plattner, R.D. (1993). Fumonisins, mycotoxins produced by Fusarium species: biology, chemistry, and significance. Annual Review of Phytopathology, 31, 233–252. Rheeder, J.P., Marasas, W.F. and Vismer, H.F. (2002). Production of fumonisin analogs by Fusarium species. Applied and Environmental Microbiology, 68(5), 2101–2105. SPSS. (2012). SPSS for Windows version 20, SPSS: Chicago, IL, USA. Tóth, Á. et al. (2000). Effect of low doses of the mycotoxin fumonisin B1 on the body weight gain, feed intake and feed conversion rate of pigs. Agriculture, 6, 149–151. Â

Assessment of the impact of the IARC Monograph Vol. 121 on the safety of the substance styrene (FCM No 193) for its use in plastic food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) was requested by the European Commission to re‐evaluate the safety of styrene (FCM No 193) for use in plastic food contact materials (FCM) following the classification by the International Agency for Research on Cancer (IARC) as ‘probably carcinogenic to humans’. The IARC Monograph pertains to hazard identification, based on studies on high‐dose occupational exposures by inhalation and animal studies, also mainly by inhalation. The Panel considered that the IARC conclusions cannot be directly applied to the evaluation of risks for consumers from the oral exposure to styrene, but also concluded that, based on the data provided in the IARC Monograph and by the industry, a concern for genotoxicity associated with oral exposure to styrene cannot be excluded. The migration of styrene into foods packed in styrenic plastics is below 10 μg/kg for the majority of the foods, but up to 230 μg/kg was reported. Migration tends to be high for contact with fatty foods, and/or with high surface to volume ratios of the FCM. Dietary exposure of the consumers to styrene migrating from styrenic plastics was estimated in the order of 0.1 μg/kg body weight (bw) per day. It is in the same range as exposure from styrene present in foods as such. The dietary exposure (food component plus migration from styrenic plastics) is similar or lower than that by inhalation in the general population. Taking the human exposure data into account, the Panel concluded that a systematic review of genotoxicity and mechanistic data, comparative toxicokinetics and analysis of species differences is required for assessing the safety of styrene for its use in FCM.

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.

The IARC Monographs: Updated Procedures for Modern and Transparent Evidence Synthesis in Cancer Hazard Identification.

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert Advisory Group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs Programme. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating and integrating evidence to identify causes of human cancer. The advancements adopted include strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention.

Public health and evidence-informed policy-making: The case of a commonly used herbicide.

Public health and evidence-informed policy-making: The case of a commonly used herbicide.

Abstract

In 2015, the International Agency for Research on Cancer (IARC) published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens.

Commentary: IARC Monographs Program and public health under siege by corporate interests.

The International Agency for Research on Cancer (IARC) evaluates causes of cancer with help from independent international experts in an open and transparent manner. Countries, research and regulatory agencies, and other organizations adopt IARC evaluations for communication of human cancer hazards, and for strategies to prevent cancer. Scientists worldwide endorse IARC cancer evaluations and process. Those with economic interests, however, challenge IARC's cancer evaluations, most recently for glyphosate and red and processed meats, and are conducting a campaign including intervention from US Congressional Representatives to discredit IARC's review process and to undermine financial support-a campaign intimidating to IARC and Working Group members. Challenges to scientific interpretations serve to advance science and should be resolved by scientific experts who do not have conflicts of interest. Such interference does not bode well for the free flow of scientific information that informs and protects the public from risks of cancer.

On the International Agency for Research on Cancer classification of glyphosate as a probable human carcinogen.

The recent classification by International Agency for Research on Cancer (IARC) of the herbicide glyphosate as a probable human carcinogen has generated considerable discussion. The classification is at variance with evaluations of the carcinogenic potential of glyphosate by several national and international regulatory bodies. The basis for the IARC classification is examined under the assumptions that the IARC criteria are reasonable and that the body of scientific studies determined by IARC staff to be relevant to the evaluation of glyphosate by the Monograph Working Group is sufficiently complete. It is shown that the classification of glyphosate as a probable human carcinogen was the result of a flawed and incomplete summary of the experimental evidence evaluated by the Working Group. Rational and effective cancer prevention activities depend on scientifically sound and unbiased assessments of the carcinogenic potential of suspected agents. Implications of the erroneous classification of glyphosate with respect to the IARC Monograph Working Group deliberative process are discussed.

Critique of the IARC 100F Working Group Evaluation of Occupational Benzene Exposure: Suggestions for the October 2017 Benzene-Only Working Group Meeting.

Health agencies and institutions utilize International Agency for Research on Cancer (IARC) monographs because they are said to represent authoritative cancer evaluations and scientific references. The United States National Cancer Institute has provided support for the IARC Monographs Program for more than three decades. The Volume 100F Monograph, which was published in 2012, reports the evaluations of benzene and more than two dozen other agents performed by the IARC Working Group (WG) that met in Lyon, France from 20 to 27 October 2009. All had already been judged to be human carcinogens. This commentary discusses errors in the occupational exposure section (1.1.3) of the 100F Benzene Monograph ("monograph"). Millions of workers in developed and developing countries have long been known to be routinely exposed to benzene. Since exposures may exceed occupational exposure limits, the hope is that this commentary will be considered by the IARC benzene-only WG at its meeting in October 2017.

Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups.

Evidence regarding carcinogenic mechanisms serves a critical role in International Agency for Research on Cancer (IARC) Monograph evaluations. Three recent IARC Working Groups pioneered inclusion of the US Environmental Protection Agency (EPA) ToxCast program high-throughput screening (HTS) data to supplement other mechanistic evidence. In Monograph V110, HTS profiles were compared between perfluorooctanoic acid (PFOA) and prototypical activators across multiple nuclear receptors. For Monograph V112-113, HTS assays were mapped to 10 key characteristics of carcinogens identified by an IARC expert group, and systematically considered as an additional mechanistic data stream. Both individual assay results and ToxPi-based rankings informed mechanistic evaluations. Activation of multiple nuclear receptors in HTS assays showed that PFOA targets not only peroxisome proliferator activated receptors, but also other receptors. ToxCast assays substantially covered 5 of 10 key characteristics, corroborating literature evidence of "induces oxidative stress" and "alters cell proliferation, cell death or nutrient supply" and filling gaps for "modulates receptor-mediated effects." Thus, ToxCast HTS data were useful both in evaluating specific mechanistic hypotheses and in contributing to the overall evaluation of mechanistic evidence. However, additional HTS assays are needed to provide more comprehensive coverage of the 10 key characteristics of carcinogens that form the basis of current IARC mechanistic evaluations.

IARC use of oxidative stress as key mode of action characteristic for facilitating cancer classification: Glyphosate case example illustrating a lack of robustness in interpretative implementation

The International Agency for Research on Cancer (IARC) has formulated 10 key characteristics of human carcinogens to incorporate mechanistic data into cancer hazard classifications. The analysis used glyphosate as a case example to examine the robustness of IARC's determination of oxidative stress as “strong” evidence supporting a plausible cancer mechanism in humans. The IARC analysis primarily relied on 14 human/mammalian studies; 19 non-mammalian studies were uninformative of human cancer given the broad spectrum of test species and extensive use of formulations and aquatic testing. The mammalian studies had substantial experimental limitations for informing cancer mechanism including use of: single doses and time points; cytotoxic/toxic test doses; tissues not identified as potential cancer targets; glyphosate formulations or mixtures; technically limited oxidative stress biomarkers. The doses were many orders of magnitude higher than human exposures determined in human biomonitoring studies. The glyphosate case example reveals that the IARC evaluation fell substantially short of “strong” supporting evidence of oxidative stress as a plausible human cancer mechanism, and suggests that other IARC monographs relying on the 10 key characteristics approach should be similarly examined for a lack of robust data integration fundamental to reasonable mode of action evaluations.