The carcinogenicity of benzene. The IARC Monograph Vol 120. Kurt Straif, MD MPH PhD. PSA, Stavanger, 25 October 2018

Transcription

1 The carcinogenicity of benzene. The IARC Monograph Vol 120 Kurt Straif, MD MPH PhD PSA, Stavanger, 25 October 2018

2 The encyclopaedia of The IARC Monographs evaluate Chemicals Complex mixtures Occupational exposures Physical and biological agents Lifestyle factors carcinogens More than 1000 agents have been evaluated 120 are carcinogenic to humans (Group 1) 8 2are probably carcinogenic to humans (Group 2A) 302 are possibly carcinogenic to humans (Group 2B) Lorenzo Tomatis National and international health agencies use the Monographs As a source of scientific information on known or suspected carcinogens As scientific support for their actions to prevent exposure to known or suspected carcinogens

3 How are the IARC Monograph evaluations conducted? Procedural guidelines for participant selection, conflict of interest, stakeholder involvement & meeting conduct Separate criteria for review of human, animal and mechanistic evidence Decision process for overall evaluations

4 Systematic gathering and evaluation of original research that is available in the public domain for independent scientific review o Published methods based on international guidance o Conclusions described using internationally defined terms o Uniform, hierarchic evaluation structure Same criteria applied in all evaluations Same criteria applied to all studies Working Group comments [in square brackets] Fully referenced Monograph is published online for free download o o Systematic scientific evaluation All studies (positive and negative) are described Rationale for conclusions is given

5 Step 2: Integrate findings in overall evaluations Step 1: Categorize each line of evidence using defined terms The IARC Monographs Evaluations: A Two-Step Process Cancer in humans Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Cancer in experimental animals Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Mechanistic and other relevant data Weak, moderate, or strong evidence? Does this or can it occur in humans? Overall evaluation Group 1 Carcinogenic to humans (120) Group 2A Probably carcinogenic to humans (81) Group 2B Possibly carcinogenic to humans (299) Group 3 Not classifiable as to its carcinogenicity to humans (501) Group 4 Probably not carcinogenic to humans (1)

6 Benzene Monographs, Vol 7, 1974 Animal data Benzene has been tested only in mice by subcutaneous injection and skin application. The data reported do not permit the conclusion that carcinogenic activity has been demonstrated. Human data It is established that exposure to commercial benzene or benzene-containing mixtures may result in damage to the haematopoietic system. A relationship between such exposure and the development of leukaemia is suggested by many case reports, and this suggestion is strengthened by a case-control study from Japan.

7 Benzene Monographs, Suppl 1, 1979 Benzene has shown no evidence of carcinogenicity when tested in mice by skin application. Other animal experiments were considered to be inadequate Several case reports as well as an epidemiological case control study suggest a relationship between benzene exposure and leukaemia. 2 cohort studies showed an increased incidence of acute non-lymphocytic leukaemia in workers exposed to benzene. An additional report of a large number of leukaemia cases among a group of workers exposed to benzene. Group 1 based on sufficient evidence in humans and inadequate evidence in experimental animals

8 Benzene Monographs, Vol 29, 1982 There is limited evidence that benzene is carcinogenic in experimental animals. It is established that human exposure to commercial benzene or benzene-containing mixtures can cause damage to the haematopoietic system, including pancytopenia. The relationship between benzene exposure and the development of acute myelogenous leukaemia has been established in epidemiological studies. Reports linking exposure to benzene with other malignancies were considered to be inadequate for evaluation. There is sufficient evidence that benzene is carcinogenic to man.

9 Benzene Monographs, Suppl 4, 1982 Data on humans and on animals not re-evaluated Limited evidence for activity in short-term tests Benzene Monographs, Suppl 7, 1987 Oral administration induced neoplasms at multiple sites in males and females of both species, In mice, by inhalation increase of lymphoid neoplasms. Mouse-lung tumour bioassay by intraperitoneal injection, increase of lung adenomas in males. Exposure of rats by inhalation increased the incidence of neoplasms, mainly carcinomas, at various sites. Skin application or subcutaneous injection of benzene to mice did not produce evidence of carcinogenicity, but most of the experiments were inadequate for evaluation.

10 Benzene Monographs, Vol 100F, 2009 Sufficient evidence in humans for the carcinogenicity of benzene. Benzene causes acute myeloid leukaemia/acute non-lymphocytic leukaemia. Positive association between exposure to benzene and acute lymphocytic leukaemia, chronic lymphocytic leukaemia, multiple myeloma, and NHL. Strong evidence that benzene metabolites, acting alone or in concert, produce multiple genotoxic effects at the level of the pluripotent haematopoietic stem cell resulting in chromosomal changes in humans consistent with those seen in haematopoietic cancer. In multiple studies in different occupational populations in many countries over more than three decades a variety of genotoxic changes, including chromosomal abnormalities, have been found in the lymphocytes of workers exposed to benzene.

11 IARC Monographs, Volume 100 A Review of Human Carcinogens The volume was developed over the course of 6 meetings A. Pharmaceuticals (23 agents, Oct 2008) B. Biological agents (11 agents, Feb 2009) C. Metals, particles and fibres (14 agents, Mar 2009) D. Radiation (14 agents, June 2009) E. Lifestyle factors (11 agents, Sept 2009) F. Chemicals and related occupations (34 agents, Oct 2009) Volume 100 Workshops - Tumour (Site) Concordance between Humans and Animals - Mechanisms Involved in Human Carcinogenesis

12 10 Key Characteristics of Human Carcinogens Key characteristic: 1. Is electrophilic or can be metabolically activated 2. Is genotoxic 3. Alters DNA repair or causes genomic instability 4. Induces epigenetic alterations 5. Induces oxidative stress 6. Induces chronic inflammation 7. Is immunosuppressive 8. Modulates receptor-mediated effects 9. Causes immortalization 10. Alters cell proliferation, cell death, or nutrient supply Established human carcinogens commonly exhibit one or more characteristics Data on these characteristics can provide evidence of carcinogenicity They can also help in interpreting the relevance and importance of findings of cancer in animals and in humans. Smith MT, et al.. Env Health Persp., 124(6):713-21

13 Quantitative Risk Characterization in Monographs Preamble, 2006 A Monograph may undertake to estimate dose response relationships within the range of the available epidemiological data... A subsequent publication may be prepared by a separate WG... AG Quantitative Risk Characterization, 2013 Recommendation to summarize exposure response relationships seen in epidemiological studies Additional resources will be needed to pursue QRC AG on Priorities, 2014 AG supported recommendations by the AG on QRC to progressively include exposure response associations in the Monographs, particularly from epidemiological studies.

14 Benzene Vol 120, Exposure Characterisation Aromatic hydrocarbon, now restricted in many countries, but still produced in high volumes for use primarily as a chemical intermediate Occupational exposure can occur in diverse industries, incl. petroleum, chemical production, and manufacturing, in some countries still occurs in industries where high levels were observed historically, such as shoemaking, painting, printing, and rubber manufacturing. Ubiquitous air pollutant, component of gasoline, vehicle exhaust, industrial emissions, and tobacco smoke. Benzene concentrations in workplace and outdoor air have declined over time; with concentrations < 3 and mg/m3 in workplace and outdoor air, respectively (HIC)

15 Benzene Vol 120, Cancer in humans Important new evidence came from several large occupational cohort studies (Stenehjem et al 2015, Linet et al 2015, Schnatter et al 2012). Confirmed: Benzene causes acute myeloid leukaemia/acute non-lymphocytic leukaemia. Confirmed: Positive association between exposure to benzene and chronic lymphocytic leukaemia, multiple myeloma, and NHL. Positive associations between AML in children and environmental exposure to benzene. Positive associations between exposure to benzene and chronic myeloid leukaemia and lung cancer

16 Benzene Vol 120, Cancer in exp. Animals (I) In mice, inhalation studies, induction of tumours of the haematopoietic and lymphoid tissues, Zymbal gland carcinoma, squamous cell carcinoma of the preputial gland, forestomach squamous cell carcinoma, and lung adenoma. Oral administration, induction of tumours of the haematopoietic and lymphoid tissues, lung alveolar or bronchiolar adenoma and carcinoma, hepatocellular adenoma and carcinoma, squamous cell carcinoma of the Zymbal gland, adenoma and carcinoma of the Harderian gland, preputial gland carcinoma, ovarian tumours, malignant mammary gland tumours (females), forestomach squamous cell tumours, and pheochromocytoma Intraperitoneal injection, liver tumours and tumours of the haematopoietic and lymphoid tissues in offspring

17 Benzene Vol 120, Cancer in exp. Animals (II) In rats, after inhalation, in the offspring benzene caused tumours of the haematopoietic and lymphoid tissues, Zymbal gland carcinoma, oral cavity squamous cell carcinoma, Hepatocellular carcinomas and forestomach carcinoma in situ. In gavage studies benzene caused tumours of the haematopoietic and lymphoid tissues, Zymbal gland carcinoma, oral cavity squamous cell carcinoma, skin carcinoma and forestomach carcinoma in situ In 3 different genetically modified mouse models of different genetic backgrounds, benzene induced tumours of the haematopoietic and lymphoid tissues by oral administration, whole-body inhalation, or skin application;

18 Benzene, Key Characteristics of Carcinogens Benzene is easily absorbed, widely distributed, and extensively metabolised, yielding a complexity of reactive electrophiles via multiple metabolic pathways in various tissues, including bone marrow Strong evidence, including in exposed humans, shows that benzene is metabolically activated, induces oxidative stress, is genotoxic, is immunosuppressive, and causes haematotoxicity. Strong evidence from experimental studies shows that benzene causes genomic instability, inhibiting topoisomerase II; modulates receptor-mediated effects relevant to aryl hydrocarbon receptor, and induces apoptosis.

19 Benzene, Quantitative Risk Characterization WG investigated shape and slope of the exposure response function for AML in meta-regression analyses of 6 published occupational cohort studies with suitable data. Relationship of benzene exposure with the log relative risk was well described by a linear model. Slope moderately sensitive to whether a cohort study of rubber hydrochloride workers, which had the highest exposure estimates, was included in the model.

20 Regression model of cumulative benzene exposure and AML, including fitted curve and confidence bands

21 Benzene, Quantitative Risk Characterization WG investigated shape and slope of the exposure response function for AML in meta-regression analyses of 6 published occupational cohort studies with suitable data. Relationship of benzene exposure with the log relative risk was well described by a linear model. Slope moderately sensitive to whether a cohort study of rubber hydrochloride workers, which had the highest exposure estimates, was included in the model. Majority of human studies that reported exposure response data for benzene and endpoints relevant to KC (ie, micronuclei, chromosomal aberrations, and leukocyte counts) an exposure response gradient was reported.

22 Acknowledgements The IARC Monographs and Handbooks are supported by grants from U.S. National Cancer Institute (since 1982) European Commission, DG Employment, Social Affairs and Inclusion (since 1986) U.S. National Institute of Environmental Health Sciences (since 1992) Institut National du Cancer (INCa), France Mange takk!

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24 Conflicts of interest: management and disclosure Independent evaluations by the world s leading experts world s leading experts free from conflicts of interests Only these experts draft text and perform evaluations, BUT other scientists can participate in defined roles: Invited Specialists Representatives of national and international health agencies Observers IARC Secretariat Real or apparent conflicts of interest publicly announced: In advance (2 months before the in-person meeting) In the published The Lancet Oncology summaries In the published volume of Monographs

25 Subgroup work Cancer in humans Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Cancer in experimental animals Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Mechanistic and other relevant data Mechanistic data weak, moderate, or strong? Mechanism likely to be operative in humans? Overall evaluation Group 1 Group 2A Group 2B Group 3 Group 4 Carcinogenic to humans Probably carcinogenic to humans Possibly carcinogenic to humans Not classifiable as to its carcinogenicity to humans Probably not carcinogenic to humans

26 Evaluating human data (Subgroup 2) Cancer in humans Preamble Part B, Section 6(a) Cancer in experimental animals Mechanistic and other relevant data Sufficient evidence Limited evidence Inadequate evidence Causal relationship has been established Chance, bias, and confounding could be ruled out with reasonable confidence Causal interpretation is credible Chance, bias, or confounding could not be ruled out Studies permit no conclusion about a causal association Several adequate studies covering the full range of Evidence suggesting exposure levels are mutually consistent in not showing a lack of carcinogenicity positive association at any observed level of exposure Conclusion is limited to cancer sites and conditions studied

27 Evaluating experimental animal data (Subgroup 3) Cancer in humans Cancer in experimental animals Preamble Part B, Section 6(b) Mechanistic and other relevant data Sufficient evidence Limited evidence Inadequate evidence Causal relationship has been established through either: - Multiple positive results (2 species, studies, sexes of GLP) - Single unusual result (incidence, site/type, age, multi-site) Data suggest a carcinogenic effect but: (e.g.) single study, benign tumours only, promoting activity only Studies permit no conclusion about a carcinogenic effect Evidence suggesting lack of carcinogenicity Adequate studies in at least two species show that the agent is not carcinogenic Conclusion is limited to the species, tumour sites, age at exposure, and conditions and levels of exposure studied

28 Evaluating mechanistic and other data (Subgroup 4) Cancer in humans Cancer in experimental animals Mechanistic and other relevant data Preamble Part B, Section 6(c) Are the mechanistic data weak, moderate, or strong? Have the mechanistic events been established? Are there consistent results in different experimental systems? Is the overall database coherent? Has each mechanism been challenged experimentally? Do studies demonstrate that suppression of key mechanistic processes leads to suppression of tumour development? Is the mechanism likely to be operative in humans? Are there alternative explanations? Could different mechanisms operate in different dose ranges, in humans and experimental animals, or in a susceptible group? Note: an uneven level of support for different mechanisms may reflect only the resources focused on each one

29 The plenary sessions will combine the human and experimental evaluations EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 (carcinogenic to humans) Limited EVIDENCE IN HUMANS Group 2A (probably carcinogenic) Group 2B (possibly carcinogenic) (exceptionally, Group 2A) Inadequate Group 2B (possibly carcinogenic) Group 3 (not classifiable) ESLC Group 4

30 Overall carcinogenicity evaluation

31 Occupational exposure as a Cancer in humans Painter (Vol 98) There is sufficient evidence in humans for the carcinogenicity of occupational exposure as a painter. Occupational exposure as a painter causes cancers of the lung and urinary bladder. There is limited evidence in humans, based primarily on studies of maternal exposure, that painting is associated with childhood leukaemia. Overall evaluation Occupational exposure as a painter is carcinogenic to humans (Group 1).