Protective role of SARS-CoV-2 anti-S IgG against breakthrough infections among European healthcare workers during pre and post-Omicron surge-ORCHESTRA project.

PURPOSE: Anti SARS-CoV-2 vaccination initially showed high effectiveness in preventing COVID-19. However, after the surge of variants of concern, the effectiveness dropped. Several studies investigated if this was related to the decrease of the humoral response over time; however, this issue is still unclear. The aim of this study was to understand whether SARS-CoV-2 anti-S IgG levels can be used to predict breakthrough infection risk and define the timing for further booster doses administration. METHOD: Within the framework of the ORCHESTRA Project, over 20,000 health workers from 11 European centers were enrolled since December 2020. We performed two Cox proportional hazards survival analyses regarding pre-Omicron (from January to July 2021) and Omicron (December 2021-May 2022) periods. The serological response was classified as high (above the 75th percentile), medium (25th-75th), or low (< 25th). RESULTS: Seventy-four (0.33%) and 2122 (20%) health workers were infected during the first and second periods, respectively. Both Cox analyses showed that having high anti-S titer was linked to a significantly lower risk of infection as compared to having medium serological response [HR of high vs medium anti-S titer = 0.27 (95% CI 0.11-0.66) during the first phase, HR = 0.76 (95% CI 0.62-0.93) during the second phase]. CONCLUSION: Vaccine effectiveness wanes significantly after new variants surge, making anti-S titer unsuitable to predict optimal timing for further booster dose administration. Studies on other immunological indicators, such as cellular immunity, are therefore needed to better understand the mechanisms and duration of protection against breakthrough infection risk.

Moderate alcohol consumption during pregnancy increases potency of two different drugs (the antifungal fluconazole and the antiepileptic valproate) in inducing craniofacial defects: prediction by the in vitro rat whole embryo culture.

The prenatal exposure to ethanol (Eth), fluconazole (FLUCO) and sodium valproate (VPA) is related to effects on development, producing characteristic syndromic pictures. Among embryotoxic effects described for the three molecules, the alteration on craniofacial morphogenesis is a common feature in humans and animal models, including rodent embryos developed in vitro. The aim of the present work is to evaluate the developmental effects of low Eth serum concentration (17 mM, corresponding to the legal limit to drive in UK, USA, Canada, and many other countries) in mixture with increasing realistic concentrations of the antifungal drug FLUCO (62.5-500 µM) or with increasing realistic concentrations of the antiepileptic drug VPA (31.25-250 µM). Groups exposed to Eth alone (17-127.5 mM), FLUCO alone (62.5-500 µM) or VPA alone (31.25-750 µM) were also included. The chosen alternative animal model was the post-implantation rat whole embryo culture (WEC). E9.5 embryos were exposed in vitro to the test molecules during the whole test period (48 h, corresponding to the developmental stages characteristics of any vertebrate, for human embryos post-fertilization days 23-31). Data were statistically analyzed and processed for modelling applying the benchmark dose (BMD) and relative potency factor (RPF) approaches. Concentration-related effects on facial outcomes were observed in all experimental groups, with a significant enhancement in the groups co-exposed with Eth in comparison to the single exposures. Data obtained by the present work suggest an additional alert for the assumption of even low levels of alcohol in pregnant women during FLUCO or VPA therapy.

Non-sugar sweeteners and cancer: Toxicological and epidemiological evidence.

Several toxicological and epidemiological studies were published during the last five decades on non-sugar sweeteners (NSS) and cancer. Despite the large amount of research, the issue still continues to be of interest. In this review, we provided a comprehensive quantitative review of the toxicological and epidemiological evidence on the possible relation between NSS and cancer. The toxicological section includes the evaluation of genotoxicity and carcinogenicity data for acesulfame K, advantame, aspartame, cyclamates, saccharin, steviol glycosides and sucralose. The epidemiological section includes the results of a systematic search of cohort and case-control studies. The majority of the 22 cohort studies and 46 case-control studies showed no associations. Some risks for bladder, pancreas and hematopoietic cancers found in a few studies were not confirmed in other studies. Based on the review of both the experimental data on genotoxicity or carcinogenicity of the specific NSS evaluated, and the epidemiological studies it can be concluded that there is no evidence of cancer risk associated to NSS consumption.

The University of Padua salivary-based SARS-CoV-2 surveillance program minimized viral transmission during the second and third pandemic wave.

BACKGROUND: The active surveillance of students is proposed as an effective strategy to contain SARS-CoV-2 spread and prevent schools' closure. Saliva for molecular testing is as sensitive as naso-pharyngeal swab (NPS), self-collected and well accepted by participants. This prospective study aimed to verify whether the active surveillance of the Padua University employees by molecular testing of self-collected saliva is an effective and affordable strategy for limiting SARS-CoV-2 spread. METHODS: A surveillance program based on self-collection of saliva every 2 weeks (October 2020-June 2021) was conducted. Among 8183 employees of the Padua University, a total of 6284 subjects voluntarily took part in the program. Eight collection points guaranteed the daily distribution and collection of barcoded salivary collection devices, which were delivered to the laboratory by a transport service for molecular testing. Quarantine of positive cases and contact tracing were promptly activated. RESULTS: Among 6284 subjects, 206 individuals were SARS-CoV-2 positive (99 by salivary testing; 107 by NPS performed for contact tracing or symptoms). The cumulative SARS-CoV-2 incidence in this cohort was 3.1%, significantly lower than that of employees not in surveillance (8.0%), in Padua (7.1%) and in the Veneto region (7.2%). Employees with positive saliva results were asymptomatic or had mild symptoms. The levels of serum antibodies after 3 months from the infection were correlated with age and Ct values, being higher in older subjects with greater viral loads. CONCLUSIONS: Salivary-based surveillance with contact tracing effectively allowed to limit SARS-CoV-2 contagion, also in a population with a high incidence.

A new approach to the classification of carcinogenicity.

Concern over substances that may cause cancer has led to various classification schemes to recognize carcinogenic threats and provide a basis to manage those threats. The least useful schemes have a binary choice that declares a substance carcinogenic or not. This overly simplistic approach ignores the complexity of cancer causation by considering neither how the substance causes cancer, nor the potency of that mode of action. Consequently, substances are classified simply as "carcinogenic", compromising the opportunity to properly manage these kinds of substances. It will likely be very difficult, if not impossible, to incorporate New Approach Methodologies (NAMs) into binary schemes. In this paper we propose a new approach cancer classification scheme that segregates substances by both mode of action and potency into three categories and, as a consequence, provides useful guidance in the regulation and management of substances with carcinogenic potential. Examples are given, including aflatoxin (category A), trichlorethylene (category B), and titanium dioxide (category C), which demonstrate the clear differentiation among these substances that generate appropriate levels of concern and management options.

The codification of hazard and its impact on the hazard versus risk controversy.

The long running controversy about the relative merits of hazard-based versus risk-based approaches has been investigated. There are three levels of hazard codification: level 1 divides chemicals into dichotomous bands of hazardous and non-hazardous; level 2 divides chemicals into bands of hazard based on severity and/or potency; and level 3 places each chemical on a continuum of hazard based on severity and/or potency. Any system which imposes compartments onto a continuum will give rise to issues at the boundaries, especially with only two compartments. Level 1 schemes are only justifiable if there is no variation in severity, or potency or if there is no threshold. This is the assumption implicit in GHS/EU classification for carcinogenicity, reproductive toxicity and mutagenicity. However, this assumption has been challenged. Codification level 2 hazard assessments offer a range of choices and reduce the built-in conflict inherent in the level 1 process. Level 3 assessments allow a full range of choices between the extremes and reduce the built-in conflict even more. The underlying reason for the controversy between hazard and risk is the use of level 1 hazard codification schemes in situations where there are ranges of severity and potency which require the use of level 2 or level 3 hazard codification. There is not a major difference between level 2 and level 3 codification, and they can both be used to select appropriate risk management options. Existing level 1 codification schemes should be reviewed and developed into level 2 schemes where appropriate.

Health effects of living near an incinerator: A systematic review of epidemiological studies, with focus on last generation plants.

Huge reductions in incinerators' emissions occurred over time, and results of older studies cannot be directly generalized to modern plants. We conducted a systematic review of the epidemiologic evidence of the health effects of incinerators, classifying plants in three generations, according to emission limits. A systematic search identified 63 epidemiologic studies, published in English, investigating health effects of incinerators on humans. We focused on cancer, cardio-cerebrovascular diseases (CVD) and respiratory diseases, pregnancy outcomes and congenital anomalies. Only six studies in the general population were on third generation incinerators providing data on pregnancy outcomes and congenital anomalies. Given the heterogeneity of methods, the abundance of ecological/semi-ecological studies and the lack of reliable quantitative measures of exposure in several studies we did not perform any meta-analysis. No excesses emerged concerning all cancers and lung cancer. An excess of non-Hodgkin lymphoma was reported in some earlier studies, but not for second generation plants. Possible excesses of soft tissue sarcomas were confined to earlier incinerators and the areas closer to the plants. No clear association emerged for CVD and diseases of the respiratory system. Several different pregnancy outcomes were considered, and no consistent association emerged, in spite of a few positive results. Studies were negative for congenital anomalies as a whole. Sporadic excesses were reported in a few studies for specific types of anomalies, but no consistent pattern emerged. Evaluation of the evidence was hindered by heterogeneity in reporting and classification of outcomes across studies. Direct evidence from third generation plants is scarce. Methodological issues in study design (mainly related to exposure assessment, confounding and ecological design) and analysis make interpretation of results complex. In spite of this, the overall evidence suggests that, if there were any excesses at all for older incinerators, they were modest at most. Additional monitoring of third generation plants needs to overcome methodological weaknesses.

Assessment of penconazole exposure in winegrowers using urinary biomarkers.

Penconazole (PEN) is a fungicide used in agriculture. The aim of this work was to evaluate the exposure to PEN in vineyard workers focusing on urinary biomarkers. Twenty-two agricultural workers were involved in the study; they were investigated during PEN applications and re-entry work, performed for 1-4 consecutive working days, for a total of 42 mixing and applications and 12 re-entries. Potential and actual dermal exposure, including hand exposure, were measured using pads and hand washes. Urine samples were collected starting before the first application, continuing during the work shift, and ending 48 h after the last shift. The determination of PEN in dermal samples and PEN metabolites in urine was performed by liquid chromatography tandem mass spectrometry. Dermal potential body exposure and actual total exposure showed median levels ranging from 18 to 3356µg and from 21 to 111 µg, respectively. Urinary monohydroxyl-derivative PEN-OH was the most abundant metabolite; its excretion rate peaked within 24 h after the work shift. In this period, median concentrations of PEN-OH and the carboxyl-derivative PEN-COOH ranged from 15.6 to 27.6 µg/L and from 2.5 to 10.2 µg/L, respectively. The concentration of PEN-OH during the work shift, in the 24 h after and in the 25-48 h after the work shift were correlated with actual body and total dermal exposure (Pearson's r from 0.279 to 0.562). Our results suggest that PEN-OH in the 24 h post-exposure urine is a promising candidate for biomonitoring PEN exposure in agricultural workers.

Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible.

Developments in the understanding of the etiology of cancer have undermined the 1970s concept that chemicals are either "carcinogens" or "non-carcinogens". The capacity to induce cancer should not be classified in an inflexible binary manner as present (carcinogen) or absent (non-carcinogen). Chemicals may induce cancer by three categories of mode of action: direct interaction with DNA or DNA replication including DNA repair and epigenetics; receptor-mediated induction of cell division; and non-specific induction of cell division. The long-term rodent bioassay is neither appropriate nor efficient to evaluate carcinogenic potential for humans and to inform risk management decisions. It is of questionable predicitiveness, expensive, time consuming, and uses hundreds of animals. Although it has been embedded in practice for over 50 years, it has only been used to evaluate less than 5% of chemicals that are in use. Furthermore, it is not reproducible because of the probabilisitic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design. The modes of action that lead to the induction of tumors are already considered under other hazardous property categories in classification (Mutagenicity/Genotoxicity and Target Organ Toxicity); a separate category for Carcinogenicity is not required and provides no additional public health protection.

Chemical carcinogenicity revisited 1: A unified theory of carcinogenicity based on contemporary knowledge.

Developments in the understanding of the etiology of cancer have profound implications for the way the carcinogenicity of chemicals is addressed. This paper proposes a unified theory of carcinogenesis that will illuminate better ways to evaluate and regulate chemicals. In the last four decades, we have come to understand that for a cell and a group of cells to begin the process of unrestrained growth that is defined as cancer, there must be changes in DNA that reprogram the cell from normal to abnormal. Cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from cell proliferation especially if sustained. Chemicals that act via direct interaction with DNA can induce cancer because they cause mutations which can be carried forward in dividing cells. Chemicals that act via non-genotoxic mechanisms must be dosed to maintain a proliferative environment so that the steps toward neoplasia have time to occur. Chemicals that induce increased cellular proliferation can be divided into two categories: those which act by a cellular receptor to induce cellular proliferation, and those which act via non-specific mechanisms such as cytotoxicity. This knowledge has implications for testing chemicals for carcinogenic potential and risk management.

Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humans.

Over 50 years, we have learned a great deal about the biology that underpins cancer but our approach to testing chemicals for carcinogenic potential has not kept up. Only a small number of chemicals has been tested in animal-intensive, time consuming, and expensive long-term bioassays in rodents. We now recommend a transition from the bioassay to a decision-tree matrix that can be applied to a broader range of chemicals, with better predictivity, based on the premise that cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from sustained cell proliferation. The first step is in silico and in vitro assessment for mutagenic (DNA reactive) activity. If mutagenic, it is assumed to be carcinogenic unless evidence indicates otherwise. If the chemical does not show mutagenic potential, the next step is assessment of potential human exposure compared to the threshold for toxicological concern (TTC). If potential human exposure exceeds the TTC, then testing is done to look for effects associated with the key characteristics that are precursors to the carcinogenic process, such as increased cell proliferation, immunosuppression, or significant estrogenic activity. Protection of human health is achieved by limiting exposures to below NOEALs for these precursor effects. The decision tree matrix is animal-sparing, cost effective, and in step with our growing knowledge of the process of cancer formation.

Obfuscating transparency?

Several recent and prominent articles in Science and Nature deliberately mischaracterized the nature of genuine scientific evidence. Those articles take issue with the United States Environmental Protection Agency's recent proposal to structure its policies and rules only from studies with transparently published raw data. The articles claim it is an effort to obfuscate with transparency, by eliminating a host of studies not offering raw data. A remarkable declaration by a Science editorial is that properly trained experts can verify the scientific evidence of studies without access to raw data, We assert the Agency's proposal must be sustained. Transparency in reporting is a fundamental ethical imperative of objective scientific research justifying massive official regulations and policies. Putative hazards bereft of independent scientific evidence will continue to stoke public anxieties, calling for precautionary regulations and policies. These should rely not on spurious science but on transparent tradeoffs between the smallest exposures compatible with utility and with social perceptions of affordable precaution.

Exposure to PFOA and PFOS and fetal growth: a critical merging of toxicological and epidemiological data.

Toxicological and epidemiological evidence on the association between perfluorooctanoic acid (PFOA) or perfluorooctane sulfonic acid (PFOS) and birth/fetal weight was assessed. An extensive search for toxicological information in rats and mice, and a systematic search for epidemiological evidence were conducted. The linear regression coefficient (LRC) of birth weight (BrthW) on PFOA/PFOS was considered, and separate random effects meta-analyses for untransformed (i.e. not mathematically transformed) and log-transformed values were performed. Toxicological evidence: PFOA: 12 studies (21 datasets) in mice showed statistically significant lower birth/fetal weights from 5 mg/kg body weight per day. PFOS: most of the 13 studies (19 datasets) showed lower birth/fetal weights following in utero exposure. Epidemiological evidence: Sixteen articles were considered. The pooled LRC for a 1 ng/mL increase in untransformed PFOA (12 studies) in maternal plasma/serum was -12.8 g (95% CI -23.2; 2.4), and -27.1 g (95% CI -50.6; -3.6) for an increase of 1 loge ng/mL PFOA (nine studies). The pooled LRC for untransformed PFOS (eight studies) was -0.92 g (95%CI -3.4; 1.6), and for an increase of 1 loge ng/mL was -46.1(95% CI -80.3; -11.9). No consistent pattern emerged for study location or timing of blood sampling. CONCLUSIONS: Epidemiological and toxicological evidence suggests that PFOA and PFOS elicit a decrease in BrthW both in humans and rodents. However, the effective animal extrapolated serum concentrations are 102-103 times higher than those in humans. Thus, there is no quantitative toxicological evidence to support the epidemiological association, thus reducing the biological plausibility of a causal relationship.

A framework for cumulative risk assessment in the 21st century.

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health.

Blood lead levels following consumption of game meat in Italy.

The aim of this study was to measure lead (Pb) levels in blood (Pb-blood) in consumers of game meat, taking into account other possible sources of lead exposure. A spot blood sample was obtained from 95 subjects, and a questionnaire was used to collect general information and data on game meat consumption, hunting, wine drinking and other possible sources of lead exposure. Pb-blood was measured by inductively coupled plasma-mass spectrometry. Pb-blood was not influenced by age, sex, residence in an urban or rural area, consumption of game meat, tobacco smoking or hobbies associated with potential exposure to lead, and median Pb-blood was 1.7 (5th-95th percentile 1.0-5.3)µg/dL and 3.4 (0.9-6.1)µg/dL for game meat non-eaters and eater, respectively. A multiple linear regression analysis (containing the covariates sex, age, hunting, wine drinking, game meat consumption, tobacco smoking, shooting range, and occupational exposure) found an association with hunting (Pb-blood almost double in hunters) and wine drinking (40% higher in drinkers) but not with consumption of game meat or other parameters. Whether the higher Pb-blood level was due to inhalation of lead fumes while shooting with lead ammunition, to handling lead ammunition or both could not be ascertained.

[Classification and risk assessment: complementary or mutually exclusive approaches?] / Classificazione delle sostanze e valutazione del rischio chimico: approcci complementari o incompatibili?

OBJECTIVES: Most classification schemes are based on hazard identification: this is particularly true for carcinogenic and reproductive effects. METHODS: These schemes are no longer adequate to take adequate decisions on risk management, and they appear outmoded. In addition, the induce communication and perception problems in the population, causing health scares and anxiety that are difficult to control and recover. RESULTS: Risk assessment requires an estimation of human exposure to be compared with the safe dose for humans (exposure or intake limits) estimated after hazard characterization based on dose-response relationship. CONCLUSIONS: The risk based approaches provide quantitative information on the potency of the substance that can be compared with duration, frequency and intensity of exposure and, therefore, properly inform graded risk management decisions, in relation to the expected characteristics of exposure.

Quality check of safety data sheets for plant protection product co-formulants: hazard classification and coherence of the information. / Valutazione della qualità delle schede di sicurezza di coformulanti per prodotti fitosanitari: classificazione di pericolo e coerenza delle informazioni.

BACKGROUND: Hazard classification of chemicals can be defined as a logic-mathematical operation aimed at identifying the type and severity of the inherent hazards of a substance or a mixture. OBJECTIVES: The purpose of this study was to evaluate, in 134 safety data sheets (SDSs): i) the hazard classification and ii) its coherence with sections 9 (physical-chemical properties), 11 (toxicological properties) and 12 (ecological properties) of the SDSs. METHODS: Hazard classification and the information provided in sections 9, 11 and 12 of the SDSs have been evaluated against the criteria provided in annexes VI of the Dangerous Substance Directive, II and III of the Dangerous Preparations Directive, I and VI of the Regulation (EC) n. 1272/2008. RESULTS: Most of the analyzed SDSs of substances (62%) was associated to non-classified chemicals (61.4%), although 19.6% of them should have been classified. By contrast, 59.4% of classified substances (representing 38.6% of analyzed ones) were wrongly classified. Fifty-four %, 54% and 67% of suggested substances hazard classification were in line with sections 9 (physical-chemical properties), 11 (toxicological properties) and 12 (ecological properties). CONCLUSIONS: The proportion of hazard classification mistakes in SDS was significant, suggesting the need of more qualified experts to derive classification. The introduction of an ad hoc evaluation team, managed by a single, qualified specialist, could represent a solution to ensure the needed improvement of SDSs quality.

Problem formulation for risk assessment of combined exposures to chemicals and other stressors in humans.

When the human health risk assessment/risk management paradigm was developed, it did not explicitly include a "problem formulation" phase. The concept of problem formulation was first introduced in the context of ecological risk assessment (ERA) for the pragmatic reason to constrain and focus ERAs on the key questions. However, this need also exists for human health risk assessment, particularly for cumulative risk assessment (CRA), because of its complexity. CRA encompasses the combined threats to health from exposure via all relevant routes to multiple stressors, including biological, chemical, physical and psychosocial stressors. As part of the HESI Risk Assessment in the 21st Century (RISK21) Project, a framework for CRA was developed in which problem formulation plays a critical role. The focus of this effort is primarily on a chemical CRA (i.e., two or more chemicals) with subsequent consideration of non-chemical stressors, defined as "modulating factors" (ModFs). Problem formulation is a systematic approach that identifies all factors critical to a specific risk assessment and considers the purpose of the assessment, scope and depth of the necessary analysis, analytical approach, available resources and outcomes, and overall risk management goal. There are numerous considerations that are specific to multiple stressors, and proper problem formulation can help to focus a CRA to the key factors in order to optimize resources. As part of the problem formulation, conceptual models for exposures and responses can be developed that address these factors, such as temporal relationships between stressors and consideration of the appropriate ModFs.

Illustrative case using the RISK21 roadmap and matrix: prioritization for evaluation of chemicals found in drinking water.

The HESI-led RISK21 effort has developed a framework supporting the use of twenty-first century technology in obtaining and using information for chemical risk assessment. This framework represents a problem formulation-based, exposure-driven, tiered data acquisition approach that leads to an informed decision on human health safety to be made when sufficient evidence is available. It provides a transparent and consistent approach to evaluate information in order to maximize the ability of assessments to inform decisions and to optimize the use of resources. To demonstrate the application of the framework's roadmap and matrix, this case study evaluates a large number of chemicals that could be present in drinking water. The focus is to prioritize which of these should be considered for human health risk as individual contaminants. The example evaluates 20 potential drinking water contaminants, using the tiered RISK21 approach in combination with graphical representation of information at each step, using the RISK21 matrix. Utilizing the framework, 11 of the 20 chemicals were assigned low priority based on available exposure data alone, which demonstrated that exposure was extremely low. The remaining nine chemicals were further evaluated, using refined estimates of toxicity based on readily available data, with three deemed high priority for further evaluation. In the present case study, it was determined that the greatest value of additional information would be from improved exposure models and not from additional hazard characterization.

Classification schemes for carcinogenicity based on hazard-identification have become outmoded and serve neither science nor society.

Classification schemes for carcinogenicity based solely on hazard-identification such as the IARC monograph process and the UN system adopted in the EU have become outmoded. They are based on a concept developed in the 1970s that chemicals could be divided into two classes: carcinogens and non-carcinogens. Categorization in this way places into the same category chemicals and agents with widely differing potencies and modes of action. This is how eating processed meat can fall into the same category as sulfur mustard gas. Approaches based on hazard and risk characterization present an integrated and balanced picture of hazard, dose response and exposure and allow informed risk management decisions to be taken. Because a risk-based decision framework fully considers hazard in the context of dose, potency, and exposure the unintended downsides of a hazard only approach are avoided, e.g., health scares, unnecessary economic costs, loss of beneficial products, adoption of strategies with greater health costs, and the diversion of public funds into unnecessary research. An initiative to agree upon a standardized, internationally acceptable methodology for carcinogen assessment is needed now. The approach should incorporate principles and concepts of existing international consensus-based frameworks including the WHO IPCS mode of action framework.