Carcinogenicity of Glyphosate The IARC Monographs Dana Loomis PhD Deputy Head Monographs Programme
Overview What are the IARC Monographs? How are IARC Monograph evaluations done? IARC evaluation of pesticides 1971-2015 Glyphosate evaluation
The IARC Monographs Launched in 1971 by request of participating states to identify carcinogens More than 980 agents have been evaluated, including: Chemicals Physical exposures (radiation) Biological agents (viruses) Foods and drugs Personal habits (tobacco smoking) National and international health agencies use the Monographs As a basis for cancer prevention policy To control exposure to known or suspected carcinogens
How Are Agents Selected? Agents with evidence of human exposure and suspicion of carcinogenicity are evaluated Public call for nominations http://monographs.iarc.fr/eng/meetings/index.php Scientists, governments, NGOs, industry and individuals can nominate agents Additional nominations by IARC International expert Advisory Group on Priorities Scientists and representatives of governments and health agencies Advises IARC on priority of nominated agents
How are Evaluations Conducted? Published guidelines & criteria: Data eligibility Review of human, animal and mechanistic evidence Decision process for overall evaluations Participant selection, conflict of interest & stakeholder involvement http://monographs.iarc.fr/eng/preamble/index.php
What evidence is considered? Publicly available scientific data Peer reviewed papers Government reports Available in enough detail for critical review Cancer in animals Cancer in humans Mechanisms Overall evaluation
What are the IARC classifications? Carcinogenic to humans Group 1 Probably carcinogenic to humans Group 2A Possibly carcinogenic to humans Group 2B Not classifiable as to carcinogenicity Group 3 Probably not carcinogenic to humans Group 4 IARC classifications refer to the strength of scientific evidence (the level of certainty that the agent causes cancer) They DO NOT reflect the level of carcinogenic risk
Integrating Human and Animal Evidence EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate EVIDENCE IN HUMANS Sufficient Limited Inadequate Carcinogenic to humans (Group 1) Examples Group 1 Asbestos Tobacco smoking
Integrating Human and Animal Evidence EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate EVIDENCE IN HUMANS Sufficient Limited Inadequate Probably carcinogenic (Group 2A) Examples Group 2A DDT Tetrachloroethylene
Integrating Human and Animal Evidence EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate EVIDENCE IN HUMANS Sufficient Limited Inadequate Possibly carcinogenic (Group 2B) Possibly carcinogenic (Group 2B) Examples Group 2B Chloroform Styrene
Integrating Human and Animal Evidence EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate EVIDENCE IN HUMANS Sufficient Limited Inadequate Examples Caffeine Sulphur dioxide Not classifiable (Group 3)
Mechanistic Modifications when human data are less than sufficient EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate EVIDENCE IN HUMANS Sufficient Limited Inadequate Group 1 (carcinogenic to humans) Group 2A Group 2B (possibly carcinogenic) (probably carcinogenic) Group 2B (possibly carcinogenic) (exceptionally, Group 2A) Group 3 (not classifiable) Strong evidence in exposed humans
Who does the evaluation? Attend meetings but do not write reviews or contribute to evaluations IARC Secretariat Coordinates all aspects of the evaluation Working Group Independent scientists without conflict of interest Review science and develop evaluations Invited Specialists Experts with relevant knowledge but a competing interest Representatives of governments and health agencies Observers Scientists with a competing interest: observe but do not influence outcomes
What are the key strengths of the IARC evaluations are a reference worldwide 1. Independence Review by the world s leading experts without vested interests 2. Rigorous scientific review and evaluation Uniform evaluation system using objective criteria Guidelines developed by independent scientists 3. Transparency IARC Monograph evaluations? Published procedures All data are in the public domain for independent scientific review
IARC Evaluations of Pesticides 86 pesticides and pesticide classes evaluated 1971-2015. Classification Number Details/Comments Group 1 2 Arsenic and arsenical compounds, including pesticides; Lindane Group 2A 8 Captafol; DDT; Diazinon; Dimethylcarbamoyl chloride; Ethylene dibromide; Glyphosate; Malathion Group 2B 26 Examples evaluated in 2015: Parathion, Tetrachlorvinphos Group 3 48 *Evaluated in 2015
Herbicides evaluated by IARC Agent Classification Year Glyphosate Probably carcinogenic (Group 2A) 2015 2,4-D Possibly carcinogenic (Group 2B) 2015 Chlorophenoxy herbicides Possibly carcinogenic (Group 2B) 1987 Atrazine Not classifiable (Group 3) 1999 Simizine Not classifiable (Group 3) 1999
Selecting Pesticides for Evaluation - Nominations and Expert Advice 2014 Advisory Group Priorities based on human exposure and availability of new scientific data
Selecting Pesticides for Evaluation - Chemoinformatic data mapping An objective software tool for searching scientific data ~1000 pesticides mapped A. Organophosphates B. Organochlorines Node size is proportional to number of papers; colour indicates number of epidemiology papers (red=largest numbers)
IARC Evaluation of Glyphosate Probably carcinogenic to humans (Group 2A) Limited evidence of carcinogenicity in humans Sufficient evidence of carcinogenicity in experimntal animals Strong mechanistic evidence for genotoxicity
Glyphosate Monograph Scientific & public engagement Search for data Search for experts Critical scientific review In-Person Meeting (3-10 March 2015) Meeting announced (March 2014): Preliminary List of Agents Call for Data and Experts Request for Observer Status WHO CoI form posted Participants (and DOI) announced (Jan. 2015) The Lancet Oncology publication (March 2015) Monograph publication (July 2015) References shared with health agencies (April 2015)
Meeting Participants Working Group 17 scientists from 11 countries 1 Invited Specialist Observers 3 pesticide industry 3 academic institutions 4 Representatives of government agencies IARC Secretariat
What information was considered? o ~1000 studies identified and screened o Laboratory studies Pure glyphosate, glyphosate formulations Cancer in mice, rats DNA damage (genotoxicity) o Human studies (real-world exposures) Cancer in humans farmers, other workers DNA damage community residents before and after spraying Published Monograph: >250 references
Cancer in Humans Studies of exposed workers provide limited evidence for Non- Hodgkin lymphoma (a rare type of cancer) 1) Case-control studies Sweden, Canada, US 2592 NHL cases Increased risks, not explained by other pesticides 2) Cohort study (Ag Health Study) US, 2 states 92 NHL cases Small non-significant increase in risk 3) Meta-analysis Objective method to combine all studies Increased risks
Cancer in Animals Positive results in 2 of 2 studies of mice fed glyphosate Rare cancers: extremely important in assessing human risk.but challenging to detect signal from background noise o High statistical significance o Benign, malignant cancers; no toxicity Sufficient evidence of carcinogenicity in animals
Mechanisms of Cancer 10 Key Characteristics of Carcinogens Key characteristic Strength of Evidence 1. Electrophilic Not electrophilic 2. Genotoxic Strong (glyphosate and formulations) 3. Alters DNA repair No data 4. Epigenetic alterations No data 5. Oxidative Stressor Strong (glyphosate, formulations, and metabolite) 6. Induces chronic inflammation No data 7. Immunosuppressant Weak 8. Receptor-mediated effects Weak 9. Immortalization No data 10. Alters cell proliferation & death Weak Operates in humans? Can operate in humans Can operate in humans
Damage to DNA (Genotoxicity) Residents in sprayed communities Strong evidence, glyphosate formulations: Exposed community residents Experiments using: Human cells Animal cells Mammals and non-mammals Negative in bacteria DNA and chromosome damage in blood Strong evidence, glyphosate: No studies in exposed humans Experiments using: Human cells Animal cells Mammals and non-mammal Negative in bacteria
Summary: glyphosate hazard evaluation Cancer in experimental animals Sufficient evidence Studies of pure glyphosate Rare cancers in valid studies Mechanisms (DNA damage) Strong evidence Studies of real-world exposures Experimental studies of pure glyphosate Experimental studies of glyphosate formulations Cancer in humans (NHL) Limited evidence Studies of real-world exposures Glyphosate formulations in different regions at different times Overall Evaluation Group 2A, Probably carcinogenic to humans
What happens next? Does IARC set standards or make policy recommendations? No. It remains the responsibility of national and international agencies to limit exposures to carcinogens identified by IARC.
What happens next? What can happen after IARC classifications? A risk assessment- to help understand level of risk with exposure in different settings Public health action to limit exposure to workers or the general public NOTICE OF INTENT TO LIST CHEMICALS BY THE LABOR CODE MECHANISM: TETRACHLORVINPHOS, PARATHION, MALATHION, GLYPHOSATE [09/04/15]