Consultants in Human Health, Toxicology & Regulatory Affairs Chemicals in the Environment and Risk of Cancer Lois Haighton, B.Sc., DABT November 6, 2007 Mississauga, ON

Consultants in Human Health, Toxicology & Regulatory Affairs Google Search Engine Results Generated November 3, 2007 Cancer causing chemicals in the environment –~1,660,000 results “Cancer causing chemicals in the environment” –~597 results Carcinogens in the environment –~1,820,000 results “Carcinogens in the environment” –~12,900 results

Consultants in Human Health, Toxicology & Regulatory Affairs Who is offering advice? Cancer advocacy groups Medical professionals Media Environmentalists Educators Scientists/Researchers Companies that want to sell you stuff (supplements, organic foods) (… and all of their grandmothers)

Consultants in Human Health, Toxicology & Regulatory Affairs Who should be giving advice? Scientists/Researchers who are toxicologists and epidemiologists Agencies that employ toxicologists and epidemiologists Assistance from statisticians and risk assessors

Consultants in Human Health, Toxicology & Regulatory Affairs What is Toxicology? The study of adverse effects of chemicals or physical agents on living organisms Toxicology, which began as the study of poisons, is now a multidisciplinary field. The development of modern research tools has allowed the science of toxicology to evolve as it has drawn on knowledge gains in biology, chemistry, pharmacology, biochemistry, mathematics and physics. The field of toxicology has also come to include the application of a disciplined approach to safety evaluation and risk assessment.

Consultants in Human Health, Toxicology & Regulatory Affairs Toxicology Data Lifetime carcinogenicity studies in animals, usually in rats and mice, to assess ability of a chemical to cause cancer Genotoxicity assays to assess ability of a chemical to damage DNA Standard test battery –In vitro mutagenicity (Ames Assay) –In vitro clastogenicity in mammalian cells –In vivo clastogenicity Mechanistic studies to determine mechanism or mode by which chemicals cause cancer

Consultants in Human Health, Toxicology & Regulatory Affairs Not all Rodent Carcinogens are Human Carcinogens Some cancer mechanisms occur only in certain species –Alpha 2u-globulin accumulation (male rats); d-limonene –Forestomach tumors (rodents); propionic acid –Thyroid tumors due to differences in T3/T4 metabolism (rodents); some fungicides –Liver tumors due to peroxisome proliferation (rodents); phthalates –Bladder tumours from hyperplasia due to precipitated chemicals – high exposure exceeds solubility (rodents); saccharin

Consultants in Human Health, Toxicology & Regulatory Affairs What is Epidemiology? The study of the distribution and determinants of disease or health status in a population; the study of the occurrence and causes of health effects in humans.

Consultants in Human Health, Toxicology & Regulatory Affairs Epidemiology Studies Case/Control Studies – compares individuals with disease to controls without disease Cohort Studies – study of the occurrence of disease in a group of individuals with similar jobs, exposures, etc. Retrospective Study – identifies subjects that already have diseases and looks back in time to determine potential causality Prospective Study – subjects are identified and then followed forward in time to see what diseases they develop Meta-Analysis – combines results of studies with same research objective and similar methodologies to increase statistical power

Consultants in Human Health, Toxicology & Regulatory Affairs Agencies Involved in Cancer Research National Toxicology Program (NTP) –U.S. Department of Health and Human Services –Mission: “to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology.” International Agency For Research on Cancer (IARC) –Agency of the World Health Organization –Mission: “to coordinate and conduct research on the causes of human cancer, the mechanisms of carcinogenesis, and to develop scientific strategies for cancer control. The Agency is involved in both epidemiological and laboratory research and disseminates scientific information through publications, meetings, courses, and fellowships.”

Consultants in Human Health, Toxicology & Regulatory Affairs Incidence vs. Mortality Incidence is the number of individuals with cancer in a specified time period (e.g., new cases per year) Mortality is the number of individuals that die from cancer over a specified time period (e.g., number of deaths per year) In determining cancer trends, it is necessary to distinguish between cancer incidence and mortality Important to standardize data to age

Consultants in Human Health, Toxicology & Regulatory Affairs Age-standardized breast cancer incidence and mortality rates ( )

Consultants in Human Health, Toxicology & Regulatory Affairs Annual Incidence of Female Breast Cancer (US ) Ravdin et al., 2007 NEJM 356:1670

Consultants in Human Health, Toxicology & Regulatory Affairs Identified Carcinogens NTP Publishes “Report on Carcinogens” (11 th edition) –Chemicals Known to be Human Carcinogens (n=58) –Chemicals Reasonably Anticipated to be Human Carcinogens (n=188) 6-F735-FE81-FF769DFE5509AF0A

Consultants in Human Health, Toxicology & Regulatory Affairs Identified Carcinogens IARC Monographs; classifies chemicals according to carcinogenic risk –Group 1: The agent is carcinogenic to humans (n=102) –Group 2A: The agent is probably carcinogenic to humans (n=68) –Group 2B: The agent is possibly carcinogenic to humans (n=245) –Group 3: The agent is not classifiable as to its carcinogenicity to humans (n=516) –Group 4: The agent is probably not carcinogenic to humans (n=1, caprolactam)

Consultants in Human Health, Toxicology & Regulatory Affairs Evidence Supporting that a Chemical is likely a Carcinogen Increases incidence of tumours in experimental animals Induces genotoxic responses (although not all carcinogens cause cancer by affecting DNA) Relative risks or odd ratio is clearly >1 in epidemiology studies (i.e., strong association) Epidemiology studies consistently find same association Cancer is confirmed to occur after exposure with sufficient latency period Cancer incidence is higher with greater exposure Cancer association can be explained mechanistically

Consultants in Human Health, Toxicology & Regulatory Affairs How are you exposed to chemicals in the environment? Inhalation - air pollution, exhaust Ingestion – water, food, soil Skin contact – contaminated soils

Consultants in Human Health, Toxicology & Regulatory Affairs Carcinogens in the Environment Group 1 Carcinogens Arsenic, Beryllium, Cadmium, Chromium VI, Nickel Benzene Polycyclic Aromatic Hydrocarbons (benzo[a]pyrene) Formaldehyde Radium, Radionuclides, Radiation (including solar) 2,3,7,8-Tetrachlorodibenzo-p-dioxin Chemicals in industrial emissions (e.g., vinyl chloride, ethylene oxide)

Consultants in Human Health, Toxicology & Regulatory Affairs Drugs listed as Group 1 Carcinogens (Known Human Carcinogens) Azathioprine Chlorambucil Cyclophosphamide Cyclosporin Diethylstilboestrol Estrogen-progestogen menopausal therapy Etoposide Melphalan Methoxypsoralen Tamoxifen

Consultants in Human Health, Toxicology & Regulatory Affairs Other Group 1 Carcinogens Tobacco smoke Aflatoxins (found in peanut butter) Coal-tars Wood dust Herbal remedies containing plant species of genus Aristolochia Secondhand or “environmental” tobacco smoke Various occupations (e.g., boot and shoe manufacture and repair, chimney sweeping, paving and roofing with coal-tar pitch)

Consultants in Human Health, Toxicology & Regulatory Affairs What’s in the water? Trihalomethanes including chloroform (group 2B); formed during chlorination Metals Organic chemicals detected in streams near urban sites (U.S. Geological Survey) –Steroids including estrogen –Nonprescription drugs –Insect Repellants –Detergent metabolites –Disinfectants –Plasticizers –Fire Retardants –Antibiotics Group 1 carcinogens: PAHs and estrogen

Consultants in Human Health, Toxicology & Regulatory Affairs What’s in the air? Nitrogen oxides Sulfur oxides Carbon dioxide Carbon monoxide Volatile Organic Carbons Particulate Matter Chemicals from industrial emissions

Consultants in Human Health, Toxicology & Regulatory Affairs What’s in diesel exhaust (Group 2A)? Polycyclic aromatic hydrocarbons Nitrous oxide Nitrogen dioxide Formaldehyde (Group 1) Benzene (Group 1) Sulfur dioxide Hydrogen sulfide Carbon dioxide Carbon monoxide

Consultants in Human Health, Toxicology & Regulatory Affairs Environmental Exposure to Benzene A typical nonsmoker inhales about 0.2 mg benzene/day mostly from auto exhaust or gasoline vapor emissions; other sources include environmental tobacco smoke, petrochemical plants or refineries. In comparison a typical smoker inhales roughly 2 mg benzene/day (1.8 mg from cigarettes) (10x as much) Environmental Health Perspectives, Vol 104, Suppl 6, Dec 1996

Consultants in Human Health, Toxicology & Regulatory Affairs Example: Risk of Cancer from Benzene in the Environment A range of 2.2 x to 7.8 x is the increase in the lifetime cancer risk of an individual who is exposed for a lifetime to 1 µg/m 3 benzene in air (U.S. EPA; estimated from epidemiology studies). –~ 1 additional cancer above background per 450,000 or 130,000 exposed individuals Nonsmokers 0.2 mg/day = 10 µg/m 3 (0.2 mg/day/20 m 3 /day x 1000 µg/mg = 10 µg/m 3 ) –~ 1 cancer per 45,000 or 13,000 Smokers 2 mg/day = 100 µg/m 3 –~1 cancer per 4,500 or 1,300 individuals

Consultants in Human Health, Toxicology & Regulatory Affairs Leukemia Estimated new cases of leukemia in Canada in 2007 –4200 total (Canadian Cancer Statistics 2007) –Population as of July (32,976,026) (16.5% smokers) –~1 new case of leukemia per 7,850 Canadians –0.2 mg/day ~ 612 to 2118 new cases –2 mg/day ~ 1209 to 4185 new cases Other risk factors besides environmental benzene exposures –Ionizing radiation –Employment in rubber or petroleum industries (1,3- butadiene) Leukemia accounts for ~2.6% of new cancers –Lung 14.6%; breast 14%; prostate 14%; colorectal 13%

Consultants in Human Health, Toxicology & Regulatory Affairs Cancer Risk Factors Genetics (family history) Lifestyle choices (smoking, alcohol consumption, diet) Age Some occupations Sun exposure Exposure to chemicals

Consultants in Human Health, Toxicology & Regulatory Affairs Cancer Risk Factors Need to distinguish between Environmental Risk and Risk from Chemicals in the Environment “Environmental” risks are often referring to your “personal environment” (environment vs. genetics) and may include tobacco use, diet, physical activity, and infectious diseases. About one-third of all cancer deaths are now considered to be related to dietary factors and lack of physical activity in adulthood. In comparison, carcinogens in the environment are estimated to cause less than 5% of cancer deaths.

Consultants in Human Health, Toxicology & Regulatory Affairs What protects you from developing cancer? Metabolism and excretion processes Detoxification mechanisms (e.g., superoxide anion scavenging activity by superoxide dismutases and catalase deactivation of reactive oxygen species) DNA repair mechanisms Immunosurveillance of DNA-damaged cells Programmed cell death (apoptosis) of cells carrying damaged DNA Antioxidants from the diet

Consultants in Human Health, Toxicology & Regulatory Affairs Why do these mechanisms fail? Typically cancer may occur when the concentration of the chemical and length of exposure are sufficient to overwhelm protective or detoxification mechanisms Age – weakening of body’s immune system Genetic mutation – predisposing individuals to certain cancers

Consultants in Human Health, Toxicology & Regulatory Affairs Death Risk for the 40 (&60) [&90] Year Old* AgeCauseDeath per 1000 in 10 years MenNever-SmokedSmoker 40 (60) [90]Heart attack4 (32) [223]9 (84) [335] Lung Cancer<1 (5) [6]6 (98) [133] Any Cause27 (146) [828]64 (341) [>950] Women 40 (60) [90]Heart attack1 (14) [272]3 (45) [462] Lung Cancer<1 (5) [5]4 (65) [64] Any Cause17 (105) [879]32 (199) [>950] * Statistics from Woloshin et al., 2002 JNCI 94(11):

Consultants in Human Health, Toxicology & Regulatory Affairs Canadian Cancer Statistics % of women, 44% of men will develop cancer 24% of women, 28% of men will die from cancer Lung cancer is the leading cause of cancer death Colorectal cancer is the second leading cause of cancer death The increased number of new cases is primarily due to a growing and aging population Mortality rates have declined for all cancers combined and for most types of cancer since 1994 Cancer incidence in children has been relative constant since 1985 but mortality has declined cw_2007stats_en.pdf

Consultants in Human Health, Toxicology & Regulatory Affairs Preventative Measures Quit Smoking (or kick smokers out of house) Avoid excessive alcohol consumption Eat diet high in fruits and vegetables and low in fat Exercise Get screened for common cancers (prostate, breast, colorectal) Vitamin D? Be aware of protective measures at your place of employment

Consultants in Human Health, Toxicology & Regulatory Affairs Thank you   ext 245 