Carcinogenic, mutagenic, reprotoxic (CMR) substances

Introduction

Carcinogenic, mutagenic and reprotoxic substances are often referred to as a group, due to the fact that a substance may present all three types of hazards but also due to similarities in classification and in legal approach. The abbreviation ‘CMR’ is also commonly used.

CMRs are chronically toxic and have very serious impacts on health. Over 30 million tonnes of CMRs are produced in Europe yearly^[1]. The number of workers exposed to CMRs and the severity of effects call for coordinated scientific, technical and regulatory actions to be taken in order to protect health and improve working conditions.

What are carcinogenic, mutagenic and reprotoxic substances?

Cancer is a disease characterised by uncontrolled growth of altered cells and their ability to migrate from the original site and spread to different parts of the body. Carcinogens are substances or mixtures which induce cancer or increase its incidence.

A mutation means a permanent change in the amount or structure of the genetic material in a cell. Mutagen is used for agents increasing the occurrence of mutations. Many mutagenic substances are also carcinogenic, but not all.

Reproductive toxicity is used for agents which causeadverse effects on sexual function and fertility in males and females, developmental toxicity in the offspring and effects through or via lactation. Such agents are often referred to as reprotoxins or as being reprotoxic. Some Endocrine Disrupting Chemicals exert their effects via the reproductive system.

A substance may be classified in one or more of the above categories and may present other health or physical hazards. EU legislation^[2] provides definitions for each of the three types of substances.

Classification

Classification of CMRs in the EU is based on the strength of evidence showing that they present one of the CMR types of hazards to human health. The EU legislation regarding Classification Labelling and Packaging of substances – the CLP Regulation 1272/2008^[2] – uses the hazard categories in Table 1 for substances and for mixtures that contain CMRs.

Mixtures may be classified based on the hazards of their components (as in Table 1) or based on tests for the mixture as a whole, or on data for similar mixtures.

The International Agency for Research on Cancer (IARC) uses 4 groups for carcinogen classification, also based on the strength of evidence regarding their hazard to humans^[3].

Table 1: Classification of CMR substances and mixtures according to EU legislation and IARC criteria

Source: Regulation (EC) No 1272/2008^[2], IARC^[3]

A substance can have one or more of the CMR hazards. When it has more it is classified according to the evidence for each type of hazard, for example:

• CM: benzene is carc. 1A, muta. 1B;
• CR: lead (II) chromate is carc. 1B, repr. 1A;
• MR: dibutyltin dichloride is muta. 2, repr. 1B;
• CMR: benzo(a)pyrene is carc. 1B, muta. 1B, repr. 1B;
• C or M or R: nickel dioxide is carc. 1A, trifluoroiodomethane is muta. 2, carbon monoxide is repr. 1A.

The current EU classification (CLP Regulation 1272/2008/EU) replaces the former CMR classes established by the Directive 67/548/EEC regarding dangerous substances which used categories 1, 2 and 3 instead of categories 1A, 1B and 2, respectively. However the current classification does not include substances generated during work and natural substances; for workplace carcinogens see also the chapter on European legislation below.

Hazards and mechanism of action

Carcinogens and mutagens

Carcinogenesis and mutagenesis processes and the relation between them are not completely understood but at present two mechanisms are considered: one inducing cancer by involving mutations (caused by genotoxic substances) and one that induces or promotes it by other means (caused by non-genotoxic substances).

Genotoxic agents or their metabolites induce direct changes in the genetic material (DNA) while the non-genotoxic agents are considered to be involved in other types of mechanisms, for example acting as tumour promoters. Genotoxic and non-genotoxic substances may interact at the different stages of carcinogenicity.

The body is normally programmed (by encoded genetic information) to control cell growth in order to insure development, functionality and repair of tissues. A variety of factors (including exposure to CMRs) may disturb these mechanisms and transform normal cells into malignant ones. Malignant cells do not have the same functions, nor do they multiply or die as the cells from which they are derived. They tend to proliferate fast and invade the neighbouring tissues or enter the bloodstream or lymphatic system and spread in distant parts of the body (metastasis).

Mutagens can damage the genetic material of the cells (DNA and/or chromosomes). This can lead to permanent changes: mutations. Numerous mutations occur in a lifetime. Many of them are neutral, but some can negatively affect the cells in which they occurred.

When mutations occur in germ cells (male or female reproductive cells) the changes they cause are heritable. Germ cell mutagenicity can act over several generations and cause problems like reduction of fertility, malformations, genetic diseases, embryonic death or genetically determined phenotypic alterations. Because of their mechanism of action germ cell mutagens are likely to have carcinogenic effects.

Mutations that occur in somatic cells (non-reproductive cells) can increase the likelihood of cancer, but somatic mutations are not passed along to the next generation.

Non-genotoxic carcinogens are assumed to participate in the carcinogenesis process by a mechanism not related directly to the genetic material. They have been shown to act as tumour promoters, endocrine modifiers, immuno-suppressants or inducers of tissue-specific toxicity. Some studies consider that non-genotoxic carcinogens represent about 12% of the IARC groups 1 and 2 (A, B)^[4].

An example of a non-genotoxic carcinogen is sulfuric acid mist (IARC class 1 carcinogen). At high concentrations it generates chronic irritation of the respiratory tract that results in reactive stimulation of growth and promotion of cancer. At lower exposure levels, which do not generate irritation, the carcinogen hazard has not been confirmed^[5]. Some pesticides are also non-genotoxic carcinogens.

There are differences in how each human individual responds to chemicals (metabolic fingerprint). Tissue specificity has also been noticed. Data show that certain CMRs can be associated to target organs (organs that are most affected), like nasal cancer to exposure to chromium(VI) compounds, pleural mesothelioma to asbestos exposure, scrotal cancer from polycyclic aromatic hydrocarbons like benzo[a]pyrene from soot.

The mechanism of action is important when setting strategies for risk control. For genotoxic carcinogens a non-threshold approach is generally considered. Any exposure to a genotoxic carcinogen that reaches its biological target and reacts with it increases the probability of cancer and there is no safe range of exposure levels^[6]. Exposure should be avoided or kept as low as possible.

Non-genotoxic carcinogens may be treated as threshold toxicants. No observed adverse effect levels (NOAEL) or lowest observed adverse effect levels (LOAEL) and uncertainty factors may be used to set occupational exposure limits. The Scientific Committee for Occupational Exposure Limits (SCOEL) recommends four approaches in setting OELs for carcinogens, based on their mechanism of action and on toxicological studies^[1].

Reprotoxic substances

Reproductive toxicity refers to direct and specific effects on sexual function and fertility. This includes alterations to the reproductive system (e.g. direct injury to the female and male reproductive cells), adverse effects on onset of puberty, production and transport of gamete (i.e. sperm and egg or ‘ovum’), reproductive cycle normality, sexual behaviour, fertility, parturition (childbirth), pregnancy outcomes, premature reproductive senescence (ageing) or modifications in other functions that are dependent on the integrity of the reproductive systems. Effects transmissible via lactation to breastfed babies are also included.

Health effects of reprotoxicants for pregnant women depend on when they are exposed. Exposure during the first three months of pregnancy might cause induction of metabolic disorders in the mother body, abnormal embryogenesis, birth defects or miscarriage. During the last six months, exposure could slow foetus growth, affect the development of its brain or cause premature labour. ^{[8] [9]} Not only women can be affected by reprotoxic substances, men are also at risk. Reprotoxics can affect e.g. the male steroid hormone system and have an impact on sperm quality and concentration ^[10] The development of the foetus may also be disturbed through heritable changes (epigenetic mechanisms) in egg or semen cells, causing no change in the underlying DNA sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently. There is some evidence of epigenetic effects or transgenerational effects of paternal exposure that can impact on the pregnancy outcome, e.g. increased risks of childhood cancers. ^[11]

Developmental toxicity has a broader meaning but for pragmatic purposes of EU classification (CLP Regulation), it essentially means adverse effects induced during pregnancy, or as a result of parental exposure. These effects can be manifested at any point in the lifetime of the organism. The major manifestations of developmental toxicity include death of the developing organism, structural malformations, altered growth and functional deficiency.

For example, some glycol ethers used as solvents or certain phthalates used as plasticisers may reduce the quality or number of sperm. These effects may occur in adulthood or after prenatal exposure. They may be reversible or irreversible, depending on the substance. Other known reprotoxic substances commonly found in the workplace are lead and lead compounds, which are used in the manufacture of alloys, batteries, glass, etc. Lead affects not only fertility but also the neuronal development of children after exposure before or after birth ^[12].

Endocrine disruptors

Endocrine disruptors are chemicals that can act on the endocrine system to disturb its mechanisms or to initiate processes at abnormal times in the life cycle. Many of the endocrine disruptors affect reproductive functions (are reprotoxicants), but some may influence other functions, like the thyroidal one, for example.

These chemicals can exert their effects through a number of different mechanisms:^[13]

• Simulate the biological activity of a hormone by binding to a cellular receptor, leading to false response by initiating the cell's normal response to the natural hormone at the wrong time or to an excessive extent;
• Bind to the receptor without activating it, but preventing the binding of the natural hormone;
• Bind to transport proteins in the blood, thus altering the amounts of natural hormones that are present in the circulation;
• Interfere with the metabolic processes in the body, affecting the synthesis or breakdown rates of the natural hormones.

Phthalates and nonylphenols are examples of known endocrine disruptors affecting the reproductive functions.

Hazard communication

For substances or products classified as dangerous, the label is the most concise means of hazard communication. Since 1 December 2010, substances have to be classified, labelled and packaged according to the CLP Regulation 1272/2008. Since 1 June 2015 this applies also to mixtures.

According to the CLP Regulation 1272/2008 CMR ^[2] hazards are communicated by:

• GHS pictogram, presented in figure 1 for CMRs categories 1 (A or B) and 2;
• Signal word ‘Danger’ for category 1 (A or B) and ‘Warning’ for category 2;
• Hazard statements as presented in Table 2.

The following table shows hazard statements for CMR categories.

Table 2: Hazard statements for CMR categories

Source: Regulation (EC) No 1272/2008^[2]

Hazards caused by reprotoxicants with effects on or via lactation are only communicated by hazard statements.

Safety Data Sheets (SDS) provide more information than labels. Their content has to be explained to workers and SDS should be available to all those who use hazardous substances or products.

More complex hazard communication planning may take into account the following steps:^[14]

• Defining the problem: For a good communication on dangerous substances it is crucial to analyse the problem and to understand the nature and the scope of the potential risks and hazards.
• Creating the message: A good message can only be successful if it contains reliable, complete and exhaustive information, tailored to the target group.
• Conveying the message: The channel and tools chosen to convey the message has to be selected according to the desired scope, the target group and the nature of the message.
• Reception of the message: An important stimulus in raising awareness among the target group is to involve them, to encourage them to collaborate and to present cost and benefits.
• Collect and follow-up feedback: A feedback assessment shows if the message has been understood and allows to adjust the content if necessary as well as to keep it update.

It is useful to check whether the relevant parts of the information have been understood by using theoretical tests but also by observing if workers really know how to apply the information/guidance; see e.g. checklist of EU-OSHA.^[15]

Occupational exposure

Each year, about 120,000 work-related cancer cases occur as a result of exposure to carcinogens at work in the EU, leading to approximately 80,000 fatalities annually.^[16]. The World Health Organisation believes that this is a result of the wide use of different carcinogenic substances and therefore urges governments and industry to ensure that workplaces are equipped with adequate measures to meet health and safety standards^[17]. According to the International Labour Organization (ILO) Convention C 139 carcinogenic substances must not be used in companies unless under very strict conditions, whereby every effort has to be made to replace them. ^[18]

There are many chemicals classified as CMRs. In September 2020, 1191 chemicals had a harmonised classification and labelling for carcinogenicity or mutagenicity under the EU legislation ^[19], and IARC^[20] includes more than 530 agents (not only chemicals) in categories 1 and 2 (A, B). As reliable information is provided by studies, classification and number of CMRs may change.

In 2005, the proportion of workers in France, estimated to be exposed to CMRs was approximately 15% of the working population: 13% exposed to carcinogens, 1% to mutagens and 1% to reprotoxics^[21].

However, workplace exposure tends to involve a combination of factors and it can be difficult to establish a causal link between cancer cases and exposure to a specific chemical agent. The time between exposure and cancer onset can reach 50 years ("latency period"). There is a widespread lack of harmonised and comparable data at EU level on occupational exposure to cancer risk factors. To fill this gap, the European Agency for Safety and Health at Work (EU-OSHA) has launched a survey. The survey will be developed, tested and implemented in 2021 and 2022. The first findings are expected to be published in 2023 ^[22].

Workers under 25 years of age are estimated to be exposed to carcinogenic substances more than any others: in France (2010), 15.7%, compared to 11.6% in the 25–29 category, 9.6% for those between 30 and 39, 10% between 40 and 49, and 7.4% for those 50 years and over. ^[23]

Exposure to CMRs may occur in numerous sectors. In Table 3 a few examples of carcinogens are presented to illustrate the variety of sectors and jobs where exposure occurs.

Table 3: Examples of exposure to carcinogens in different sectors of activity

Source: adapted from EUROGIP^[24]

CMRs may be present at the workplace as raw material (including impurities), intermediates, products or by-products and emissions. In case of labelled chemicals (like products) exposure hazards are easier to be identified.

When exposure to CMRs occurs in mixtures of unintentional emissions (like fumes in welding or dust from stone cutting or hard wood processing) hazards also have to be identified, communicated and controlled, as stipulated by Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens, mutagens or reprotoxic substances at work.^[25]

CMRs entering routes into organisms include inhalation (of dust, fumes, gas, vapours), ingestion (by eating, drinking, smoking with dirty hands or by accidental ingestion) and penetration through (intact or damaged) skin and mucous membranes.

Workers are rarely exposed to only a single chemical substance. Often they are exposed to several chemicals, either simultaneously or within a short period of time. Workers may also be exposed by different routes simultaneously: e.g. inhalation and dermal absorption or ingestion.^[26] The so called ‘cocktail effect’ may carry uncertain risks. Additive effects or combined effects can lead to an increase in the severity of a harmful effect. This applies not only to the combination of interfering chemical substances but also to the combination of chemical substances and physical factors such as ototoxic substances (e.g. trichloroethylene carc.1B, muta. 2) and noise.^[27] Work in shifts that involves circadian disruption (night work) classified by IARC as probably carcinogenic, might aggravate the health effects of exposure to chemical CMRs^[3].

Moreover, exposure to CMRs occurs also due to environmental pollution, food, products, or due to non-chemical factors like radiation (including sun radiation), biological factors, night shift work that disrupts the circadian rhythm and sedentary work. Some researchers discuss even stress as a carcinogenic and/or reprotoxic factor. ^[28][29] It remains however difficult to demonstrate a clear link ^[30], since also stress coping strategies such as smoking, drinking, excessive eating or drugs consumption are indirect contributors.

EU legislation

Further to the regulations on classification and labelling referred to above, legislation applicable to CMRs includes regulations for chemicals in general, for protection of workers, for general product safety, for the environment and others.

Apart from requirements linked to their registration, CMRs that meet criteria for classification in categories 1A and 1B are subject for authorisation under the REACH Regulation. The same provisions apply to substances of equivalent concern for which there is evidence of serious effects on health. Endocrine disruptors (see above) are included in this category.

Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens, mutagens or reprotoxic substances at work (CMRD) ^[25] has specific obligations for the employer as well as other measures referring to health monitoring, record keeping and exposure limits.

Directive 2004/37/EC considers carcinogens, mutagens and reprotoxic substances that meet the criteria for classification in categories 1A and 1B. When the directive was issued in 2004, the scope of the directive only included carcinogens and mutagens. In 2022 the amending Directive 2022/431/EU also brought reprotoxic substances within the scope of the directive, changing the original title the protection of workers from the risks related to exposure to carcinogens or mutagens at work to the protection of workers from the risks related to exposure to carcinogens, mutagens or reprotoxic substances at work.

Moreover, the directive not only defines ‘carcinogens’ as substances classified as carcinogenic 1a or 1B, but Annex I includes a range of processes that should also be considered as carcinogenic, in particular:

• Manufacture of auramine;
• Work involving exposure to polycyclic aromatic hydrocarbons present in coal soot, coal tar or coal pitch;
• Work involving exposure to dusts, fumes and sprays produced during the roasting and electro-refining of cupronickel mattes;
• Strong acid process in the manufacture of isopropyl alcohol;
• Work involving exposure to hardwood dusts;
• Work involving exposure to respirable crystalline silica dust generated by a work process.
• Work involving dermal exposure to mineral oils that have been used before in internal combustion engines to lubricate and cool the moving parts within the engine.
• Work involving exposure to diesel engine exhaust emissions.

Employers must take measures to reduce the use of carcinogens or mutagens by replacing them with a substance, mixture or process that is not hazardous or less hazardous. If this is not feasible other measures should be used to lower the exposure as much as possible. Measures that have to be implemented are in order of hierarchy: elimination and substitution, engineering controls (e.g. closed system, local exhaust ventilation), administrative controls and at the end the least preferred option, use of personal protective equipment (see chapter on control measures below). Stricter measures than for less hazardous substances apply to CMR substances. Measures should also be taken in case of non-routine activities (e.g. maintenance) as well as for unforeseen exposure due to incidents or accidents. Practical recommendations are provided for record keeping on exposure and medical surveillance of workers, which are to be maintained 40 years after exposure.

Health surveillance should be made prior to exposure and at regular intervals thereafter. If there are any abnormalities found that might be due to exposure to CMRs for one worker, other workers that have been similarly exposed should also be submitted to health monitoring. The risks due to CMRs should be reassessed in such cases. Health surveillance should take into consideration the long latency of cancers and the limited possibilities in early detection of CMR effects.

Directive 2003/18/EC of the European Parliament and of the Council of 27 March 2003 amending Council Directive 83/477/EEC refers to the protection of workers from the risks related to exposure to asbestos at work.

In the European Union, there are two types of Occupational Exposure Limits: binding (constraining) and indicative OELs. At EU level, binding OELs are established as atmospheric concentrations of substances to be measured at the workplace in the breathing zone of the worker. When directive 2004/37/EC was published in 2004, it included binding OELs for three carcinogenic substances: benzene, vinyl chloride monomer and hardwood dust. In the meantime, due to amendments of the directive in the period 2017-2022 38 other binding OELs have been added to annex III of the directive ^[25]. It is expected that more OELs will be added to the directive since beating cancer remains a priority both in Europe's beating cancer plan ^[31] and the OSH strategy 2021-2027^[32] In addition to the CMRD, there are binding OELs for asbestos ^[33] and inorganic lead and its compounds^[34], also with a biological BLV.

Exposure to CMRs at the workplace may cause diseases that are compulsory to be declared according to regulations of many EU countries. Examples of such recognised occupational cancers included cancers caused by asbestos dust (mesotheliomas, bronchopulmonary cancers, laryngeal cancers) and cancers of the nose / sinuses caused by wood dust.^[35].

According to Directive 94/33/EC on the protection of young people at work, young workers are not allowed to work in conditions that expose them to CMRs^[36].

Directive 92/85/EEC on safety and health at work of pregnant and breastfeeding workers provides that they should not be exposed to lead and its compounds if these are capable of being absorbed by the human organism^[37]. According to the related guidelines, in carrying out risk assessments, employers should have regard for women who are pregnant, or who have recently given birth. Prevention of exposure to CMRs must be the first priority. This directive is not only restricted to chemicals but includes all possible risk factors, whether physical, biological, organisational or psychosocial.

Prevention and control measures

The general approach for chemical risk prevention and control is also applicable to CMRs. Legislation compliance is mandatory and should form the basis of measures.

An inventory of chemicals used or produced should be kept, updated and correlated with data on CMRs from labels, SDS and other sources of reliable information. Identification of CMRs should also be done for emissions that may contain such substances or may be generated in the technological process (e.g. diesel motor emissions, wood dust or silica dust). Substances that are not identified as carcinogens by EU legislation, but are considered as such by IARC or national authorities should also be considered.

Prioritisation of identified CMRs for prevention and control should consider classification categories and may be taken into account when planning the risk assessment.

To get a correct representation of the evaluated situation risk assessment should be based on a coherent methodology supported by information collected systematically and measured data. Non-occupational factors that may increase the risk (e.g. immunosuppressive medication), this should be also considered. The results of the risk assessment should support decision making in terms of type and priority of control measures.

Elimination and substitution

Elimination is the most effective measure to avoid exposure to CMRs. This can be achieved by changing the technology or the characteristics of the final product that will make the use of CMR unnecessary. Substitution means replacing the CMR with safer substance(s). Such measures should not induce unacceptable risks for other hazards. See also tools designed for the risk management of dangerous substances, where specific tools for substitution are presented, e.g. the Column Model.

Engineering controls

Engineering controls like process (re)design, isolation/enclosure of the source of CMR emissions and local/general ventilation should be used to control risks when CMR hazards could not be eliminated. It is generally easier to implement engineering controls in the planning phase of the working process.

Automated systems can eliminate human exposure, at least in some technological phases. Changes in operating parameters may reduce the level of emissions, for example lower temperature reduces the level of emission of volatile CMR. Measures preventing chemicals from becoming airborne, for example using coarse material instead of powder or brush painting instead of spraying, can (mainly) reduce exposure by inhalation.

Isolating the source of CMR or using an enclosed operating system limits the contact of workers with these hazardous substances.

Local exhaust ventilation (like hoods or flexible pipes exhausters) and general ventilation contribute to collective protection.

Administrative controls

Administrative control measures may be used to complement engineering controls for reducing exposure level. These measures help reduce the time of exposure and the number of persons exposed. Employers must have an updated list of workers undertaking activities that carry a risk to their health and safety in terms of exposure to CMRs.

Avoiding night shifts (IARC carc. 2A), working shorter shifts, alternating tasks with ones without exposure to CMR are examples of such measures. Gender should be considered (on a case by case, non-discriminatory basis) for example when assigning jobs in which exposure is more likely to affect women/men. Maintenance, cleaning and personal hygiene are also important in reducing exposure. Safe working procedures should be elaborated and implemented.

Personal protective equipment

The use of personal protective equipment should be limited to situations when other solutions cannot be applied or are not effective enough and should only be applied temporarily.

Other measures

Employers must take appropriate steps to ensure that workers and/or their representatives receive sufficient and suitable training about:

• potential and additional health risks (like smoking);
• precautions for preventing exposure, including safe handling and storage of chemicals and wastes;
• hygiene requirements;
• protective equipment;
• measures to be taken in the event of an accident;
• emergency procedures.

Training of workers who are or may be exposed to CMRs needs not only to communicate hazards and good practices, but also to raise awareness for risks that are visible only after a long period of exposure.

There may be a period of 20-50 years of delay from the time of exposure to carcinogens to the time of clinical detection of tumours. Effects of exposure to carcinogens may not be evident during the working life of the exposed person. Therefore, workers should be taught not to rely on ‘visible’ symptoms.

Appropriate measures must also be taken to ensure that workers are able to assess whether legislation is being applied correctly. Workers and/or their representatives must be consulted about and involved in all matters related to exposure to carcinogens, mutagens and reprotoxic factors. They must be informed as soon as possible in the event of abnormal exposure.

Employers must ensure that containers, packages and installations containing carcinogens, mutagens or reprotoxicants are clearly and legibly labelled, and that warning signs are clearly displayed.

Emergency situations involving CMRs should also be addressed providing necessary means for intervention, training and periodic drills.

Monitoring of CMRs should be performed according to a strategy that will comply with legal requirements but also with the policy of the company regarding CMRs management. This should include a periodic check of the efficacy of control measures in reducing the level of exposure.

The purpose of control measures is to eliminate exposure to CMRs or to reduce the level of exposure as much as possible. If OELs are in force, compliance with such limits should be considered as a minimal objective and efforts should be made to lower exposure as much as possible below these values.

European guidelines and risk management tools

Guidelines are non-binding documents which aim to facilitate the implementation of European directives. Some practical guidelines from the European Commission setting out best practice for the prevention of risks, are listed at the EU-OSHA single entry point “Legislation" https://osha.europa.eu/en/safety-and-health-legislation/european-guidelines. Currently, there are relevant EU guidelines on:

• Substitution
• Asbestos
• Chemical agents
• Crystalline silica

There are several tools designed for the risk management of dangerous substances available, supporting risk assessment and the development of prevention and control measures, such as substitution.

EU-OSHA has also dedicated a web section on Practical tools and guidance on dangerous substances. The database brings together tools and guidance documents that have been developed by Member States, European institutions, business associations, social partners and other actors. More than 300 database entries deal with CMR^[35]. Further guidance such as good practice solutions and factsheets on specific CMR can be found on the website Roadmap on carcinogens[36].