Cancer and the Environment Lecture

Cancer and the Environment Lecture Series Alan Abelsohn MD FCFP Riina Bray MD CFPC Ontario College of Family Physicians Supported by the Saunders-Matthey Cancer Prevention Coalition Outline Breast Cancer Overview Case Pediatric Cancers Objectives  To understand how environmental exposures contribute to a large percentage of breast cancer cases  To understand how environmental exposures can lead to the development of cancer in children Breast Cancer Cancer and the Environment Lecture Series Patient Interest Wendy Mesley. CBC Marketplace. March 2006 Breast Cancer Rates Worldwide Gambia Chad India Peru Mexico Portugal Germany Israel Denmark Netherlands IARC CancerBase 2000. (Rates Per 100.000) Risk Factors  Genetic  Environmental     Reproductive hormones Diet Ionizing radiation Chemicals in the Environment Environmental Links to Breast Cancer –Scandinavian Twins Study  Contribution of inherited vs. environmental factors to breast cancer risk    Inherited factors, 27% of risk Environmental factors, 73% of risk Suggests environmental factors play a major role in determining breast cancer risk Ref: Lichtenstein et al., N. Engl. J. Med., 343:78-85, 2000 Exposure to Environmental Chemicals  Carcinogens  Endocrine disruptors CH2OPD2 Chemicals in the Workplace –What do we know?  Some evidence of higher breast cancer risk  Acid mists  Formaldehyde  Benzene  Lead oxide  Carbon tetrachloride  Methylene chloride  Ethylene Oxide  Styrene Refs: Blair and Kazerouni, Cancer Causes & Control, 8:473-490, 1997 Cantor et al., J. Occup. Environ. Med., 37:336-348, 1995 Goldberg and Labreche, Occup. Environ. Med., 53:145-156, 1996 Hansen, Am. J. Ind. Med., 36:43-47, 1999 Norman et al., Int. J. Epidemiology, 24:276-284, 1995 Spiritas et al., Br. J. Ind. Med., 48:515-530, 1991 Chemicals in the Workplace  Light at night    May disrupt the synthesis of the hormone melatonin Changes in melatonin may affect levels of estrogen Breast cancer risk is higher in women who worked the “grave yard” shift for many years Refs: Steven and Rea, Cancer Causes Control, 12:279-287, 2001 Davis et al., JNCI, 93:15571562, 2001 Hansen et al., Epidemiology, 12:74-77, 2001 Schernhammer et al, JNCI, 93:1563-1568, 2001 Chemicals in the Home –What are we exposed to?  Cape Cod Breast Study Silent Spring Institute    household exposures 89 hormone-like and cancer-causing chemicals air and dust samples of 120 Cape Cod homes      plasticizers Disinfectants flame retardants persistent organochlorine pesticides contemporary (permethrin) pesticides  Follow up Refs: Rudel et al., J. Air Waste Manage. Assoc. 51:499-513, 2001 Rudel et al., Environ. Science and Technol., 37:4543-53, 2003 Pesticides  Ontario College of Family Physicians Systematic Review 2003 Pesticides and Cancer Risk –Exposure concerns Breast Cancer Risk of Farm Women  Few studies on cancer risks of farm women; most studies on men  North Carolina Study    Overall, breast cancer rates lower in women living on or near farms In farm women who applied pesticides, breast cancer risk 2X higher if protective clothing or gloves not worn Reducing exposure reduces risk Ref: Duell et al., Epidemiology, 11:523-531, 2000 Chemicals and Breast Cancer –National Toxicology Program Types of compounds that cause mammary (breast) tumors in laboratory animals       Organic solvents Dyes and dye intermediates Chemicals used in manufacture of rubber, neoprene, vinyl and polyurethane foams Flame retardants Food additive Gasoline additives / lead scavengers       Metals use in microelectronics Medical instrument sterilizing agent Mycotoxin (toxin produced by a type of mold) Pesticides and fumigants Pharmaceuticals Rocket fuel Refs: Dunnick et al., Carcinogenesis, 16:173-170, 1995 Bennett and Davis, Environ. Mol. Mutagen. 39:150-157, 2002 Endocrine Disrupting Chemicals -What products?  Polybrominated diphenyl ethers (PBDEs) Flame retardant  Used in plastics, textiles, carpets, & furniture foam  Detected in marine life and human breast milk globally  Can stimulate breast tumors cells to grow in the lab  Plasticizers  Nonyl phenol, bisphenol A - estrogenic  Phthalates - some may cause premature breast development in children (studies from Puerto Rico)  Heavy Metals  Cadmium and arsenite - environmental estrogens  Pesticides  Early Exposures -Can they affect breast cancer risk?  Terminal end buds (TEBs)  Target for cancer-causing chemicals TEB, CD-1 mouse, 45 days old Photo whole mount collection of Snedeker and DiAugustine, 1987 TEB, Human, 13 yrs. old Ref: Howard and Gusterson, J. Mam. Gland Biol. Neoplasia, 5:119137, 2000 Other Environmental Risks       Ionizing radiation Tobacco Smoke Aromatic Amines PAHs Dry Cleaning Benzene Dry Cleaning Organic Solvents  Mammary carcinogens in laboratory  TCE, PCE in dry-cleaning  Green dry-cleaning eliminates this  Occupational studies  laundry and dry cleaning  Gas station workers  automotive repair shops Breast Cancer and the Environment Research Centres  Funded by NIEHS and NCI  4 collaborative centres: Research and community outreach  Environmental agents   animal mammary carcinogens chemicals that mimic estrogen or otherwise disrupt hormones Epidemiologic studies different ethnic groups of young girls life exposures to variety of environmental, nutritional and social factors that impact puberty .  Vulnerable periods in mammary development.     www.bcerc.org/index.htm Non-Hodgkins Lymphoma Cancer and the Environment Lecture Series Non-Hodgkins Lymphoma  17-year old Jean-Dominique Levesque-Rene developed NHL at age 11  "I am 100-per-cent sure that pesticides gave me cancer. “  Ile Bizard, Quebec.  50% of the area is golf courses  8 times more pesticides than farming herbicide 2,4-D sprayed Non-Hodgkins Lymphoma  Activist  Ban ―cosmetic‖ pesticide use  local town council  Quebec: first province to outlaw the cosmetic use of pesticides  Other municipal by-laws Non-Hodgkins Lymphoma CT Scan Abdomen Non-Hodgkins Lymphoma Diffuse Large Cell Lymph node biopsy Non-Hodgkins Lymphoma Immunophenotyping Incidence of NHL  CCO Statistics Incidence of NHL  Among most common cancers in Ontario  Young adults  Outnumber Hodgkin’s disease 6:1  39% higher in men  Rates in Ontario among the highest in world  High rates in other industrialized countries Incidence of NHL  Rate of new cases almost doubled in last 30 years  Deaths have increased 50%  Reasons are unknown  increase leveled off in younger men and woman,  ? due to slowing in rate of HIV infection Risk Factors for NHL 
 The etiology not well understood.  Immunological factors  Environmental factors Immunological  Immunosuppressive meds post transplant  Immune disorders, including AIDS  Viruses:   Epstein-Barr virus: African Burkitt’s lymphoma HIV associated aggressive B-cell lymphoma Environmental Risk Factors  Organic solvents  PCBs and Dioxins  Pesticides  Ionizing radiation  Hair Dyes Organic Solvents: Benzene  Occupational case-control studies: 4-fold increase with 10+ years of benzene exposure.  Children: Benzene suspected in association with increases in NHL among children living near railways, oil refineries, and petrochemical plants.  Increased risk with drycleaning expoures   trichloroethylene (TCE) perchloroethylene (PCE) Organic Solvents  Increased risk with dry-cleaning exposures   trichloroethylene (TCE) perchloroethylene (PCE)  Green dry-cleaning is better Dioxins and PCBs  Substantial evidence links NHL with dioxin exposure, although not all studies are in agreement  Several studies have linked higher chlorinated congeners of PCBs in adipose tissue with NHL, consistent with findings that PCBs are immunotoxic substances Pesticides: Occupational Settings  Multiple studies of elevated risk  Agricultural and forestry workers exposed to pesticides Pesticides: Children  Increased risk of childhood lymphoma (including both Hodgkin’s disease and NHL) associated with parental occupational exposure to pesticides  Decline in NHL where the herbicide 2,4-D banned >10 years (Sweden and others)  Concluded that 5% (3.0–7.7%) of NHL is attributable to 2,4-D exposure Hardell M, Eriksson M. Env Health Perspect 2003;111(14):1704–1706 . Specific Pesticides  2,4-D (Phenoxy acid herbicides)   Several studies show 50- 200% excess NHL recent review disagrees  DDT (Organochlorine pesticides)   occupational exposures to DDT case-control study examining adipose tissue levels of other organochlorine pesticides (i.e. dieldrin, oxychlordane, heptachlor)  Organophosphate insecticides Ionizing Radiation  Hiroshima survivors, Chernobyl exposure increased risk of    Leukemia Thyroid cancer Non-Hodgkin lymphoma  Radiation therapy increased risk of NHL later in life Hair Dye  Occupational and personal exposure small elevation in NHL risk  Dark hair dyes  Dyes before 1980 showed a 30% increase in NHL Pesticide Literature Review  Ontario College of Family Physicians  Sanborn M, Cole D, Kerr K, Vakil C, Sanin L, Bassil K.  Systematic Review of Pesticide Human Health Effects  April 2004 OCFP: Pesticides and NHL  32 papers on NHL  27 met the quality criteria for inclusion    Cohort studies: 11 (9 positive association, 3 with statistical significance, 2 negative) Case-control studies: 14 (12 positive association, 8 with statistical significance, 2 negative) Ecological: 2 (2 positive association).  Five studies were excluded on quality criteria OCFP: Pesticides and NHL  23/27 show associations between pesticide exposure and NHL, many with statistical significance  Exposure misclassification, a perpetual problem with cohort studies, tends to skew results towards the null, so associations in these studies may be underestimated.  Conclusion:  ―This review uncovered compelling evidence of the link between pesticide exposure and the development of NHL‖. OCFP: Recommendations  Research  esp gene-env interactions phase out cosmetic pesticide use  Political action   Education  minimize occupational and environmental exposure to pesticides  avoid use at home, on pets, and in the garden  avoid—if possible— exposure via purchased food  wear protective gear if pesticide use necessary Organic Food - Study  Organophosphorus Pesticide Exposure of Urban and Suburban Preschool Children with Organic and Conventional Diets. Curl C, Fenske R, Elgethun K. Environ Health Perspect. 2003; 111:377382. Organic Food - Study  Preschool children, Seattle  18 children organic, 21 conventional diets  24-hr urine samples organophosphate metabolites  Median total dimethyl metabolite concentration  6X higher for children with conventional diets (0.17) than for children with organic diets (0.03 µmol/L; p = 0.0003) Organic Food - Study  Conclusion: ―Organic diet reduced children's exposure levels from above to below US EPA guidelines‖. Childhood Cancers Cancer and the Environment Lecture Series Childhood Cancer Incidence and Mortality for Children under 20 Childhood Cancer by Type for Children under 20 Background  Cancer in children under 15 years old is rare accounting for less than 1% of all malignancies diagnosed each year in developed countries.  In Canada incidence is 16/100 000 children and teenagers  Second to accidents, it is the leading cause of death in those aged 1 to 19 years  Most common cancers are leukemia's, lymphomas and tumors of the nervous system.  (Trends in Environmentally Related Childhood Illnesses. Pediatrics, 2004) Background  Childhood cancers tend to differ from those diagnosed in adults in terms of their    site of occurrence, histological appearance, clinical behavior – growing rapidly, being aggressively invasive and being more responsive to chemotherapy. International Incidence of Childhood Cancer  Highest overall rate in Uganda (183/million under 15)  Lowest in India (65-108)  Intermediate rates occur in the US and UK.  Geographic variations could indicate  genetic differences in susceptibility  differences in pre-or postnatal exposure to environmental carcinogens.  The most frequently diagnosed malignancies in US include ALL and AML. Cancers with sufficient evidence to be related to environmental exposures:  Skin cancer and melanoma  Childhood leukemia  Childhood brain cancer  Thyroid carcinoma  Stomach (H.pylori in contaminated drinking water)  Lung cancer  (Children’s Task Group – 2005) Types of Agents  Radiation (ionizing and non-ionizing)  Metals (arsenic, platinum)  Fibres (asbestos)  Chemicals (benzene, aspirin)  Mixtures (paints, cigarette smoke, pharmaceutical agents)  Physical activity  Dietary constituents => 5-10%  Familial and genetic disorders  (NF1, Down syn, Ataxia Telangiectasias)  => 5-15% Etiology  With the exception of a small percentage of cases attributable to hereditary cancer syndromes (familial retinoblastoma) or genetic syndromes (Down syndrome) the etiology of most childhood cancers is unknown (75%). Epidemiologic Studies  There are challenges for future epidemiological studies of childhood cancer:     improved diagnostic classification, improved methods for exposure assessment, evaluation of data from molecular biology to generate biologically derived hypotheses, incorporation of markers of genetic susceptibility when feasible. Causation in Epidemiologic Studies  Strength of the association  Consistency of the association  Plausibility of the hypothesis  Temporal relation of the association  Coherence of the association  Biologic gradient of the exposure and the frequency of cancer Risk Factors  Only a few identified and account for a small proportion of cases:    Preconceptual exposures to germ cells or mother of father Exposures during pregnancy Exposures after birth Substances adults carry home from the workplace,  residential sources,  child care sources,  school environment sources  => inhalation, ingestion and dermal routes  Possible exposure pathways for cancer etiology in children Critical Windows of Exposure  Discrete windows of vulnerability to exogenous exposures.  Causal relationships for preconception, in utero, perinatal, infancy and postinfancy exposures and cancer occurrence in children. In Utero Exposure  There is evidence to suggest that human fetal exposure to potentially toxic or carcinogenic substances can increase cancer risk in children and young adults  Ionizing radiation and DES are the only accepted human in utero carcinogenic exposures. This is somewhat alarming. Under-recognition of Toxic Threats: Epistemological Bias WHAT WE KNOW Known Effects d an us s c of h Insert “In Harm’s Way” OH16 a ls c mi e WHAT WE DON’T KNOW Billio ns of THE “UNKNOWN UNKNOWN” Long latency effects o Th vir ne-en Ge on ns ractio nte ment i mixtu res Windows of vu ln erability Gene Rearrangement Hypothesis  There is evidence that the gene rearrangements may originate in utero due to  marijuana,  antihistamines,  DNA topoisomerase II inhibitors (anthraquinone laxative, quinolone antibiotics, dipyrone, mosquitocidals, podophyllin resin, benzene metabolites derived from cigarette smoke and air pollution, most phenolic chemicals and their metabolites, certain fruits, tea, coffee, wine, soy and cocoa),  use of folic acid  assisted reproduction technology (high levels of estrogen and related drugs)  (Lightfoot & Roman, 2003). Ionizing Radiation  Ionizing radiation and tobacco smoke have been the most extensively studied carcinogens.  Radiation can cause most forms of cancer if it concentrates in a tissue in low enough dose that it does not kill off the tissue but damages it instead (ie alpha particles).  This holds true for the thyroid cancer and bone marrow cancer (leukemia) in children.  40 years ago the Oxford Survey of Childhood Cancers found an association between diagnostic radiography of pregnant women and subsequent development of leukemia and other cancers in their children. Thyroid Cancer  1986  Chernobyl nuclear power plant explosion & fire      Iodine isotopes liberated 5 million people affected Incidence of thyroid cancer 45 x greater in high exposure vs. low exposure group Dose response relationship Before, 0 per year thyroid cancer in children, now 100’s per year Exposures Evaluated in Cohort Studies of Cancer in Children  Birth characteristics  Exposures related to area of residence  Diagnostic and therapeutic exposure to ionizing radiation  Bacille Clamette-Guerin vaccination  Intrauterine infection  Parental occupational exposure  Maternal smoking during pregnancy  (Little, 1995) Radiofrequency and Microwave Exposure  High frequency fields may indirectly promote tumor growth by facilitating absorption of carcinogenic substances into the cell. Also, neural and neuromuscular functions, higher permeability of the blood-brain barrier, stress induced changes to the immune system, changes in the hematopoietic system and cell membrane disruption Radiofrequency and Microwave Exposure  High frequency electromagnetic fields emanate from cellular phones, wireless local area networks and Bluetooth technologies, cordless telephones, industrial machines.  Some studies have indicated an enhanced cancer risk: brain tumors, leukemias and breast cancer.  Some ecological studies around the world have shown significantly enhanced rates of leukemia in exposed populations close to transmitting towers.  (Breckenkamp and Blettner, 2003). Risk Factors of Different Childhood Cancers Known, Suggestive or Limited Associations:  Interpreting Epidemiological Research: Lessons from Studies of Childhood Cancer. Pediatrics, 2003 Childhood Cancers Acute  PESTICIDES Myelogenous Leukemia (AML) paternal occupation  SOLVENTS Benzene, alcohols, chorinated solvents in paternal occupation before, during and after  NITROGEN DIOXIDE paternal before preg.  HYDROCARBONS maternal during preg Childhood Cancers Acute  SOLVENTS Lymphocytic Leukemia (ALL) Tri/perchloroethylene, CCl4: maternal occup before during and after birth  PAH, GASOLINE, EXHAUST maternal before and during ALL  Higher incidence in areas of population growth and regions with increased population movements or social contact due to new construction in formerly isolated regions  In rising levels of commuting, influxes related to war, major disasters or tourism.  (Linet,1985; Little, 1995) Magnetic Fields and Leukemia  controversy around magnetic fields especially around wire code and childhood leukemia risk.  some geographical correlation.  complexity of the relationship and the multifactorial etiologies continue to lead to ambiguity.  The functional relationship between wire codes and magnetic fields in homes is complex, involving unbalanced current, current flow on plumbing lines, idiosyncrasies of local utility practices, uncertain applicability of multi-unit dwellings and lack of uniformity across geographic areas  (Savitz and Poole, 2001). Risk Factors Cont’d  Proximity of power lines, electromagnetic fields and occurrence of acute leukemias and brain tumors => the quality and quantity of available evidence is insufficient to make definitive conclusions. Leukemia  Breast-feeding on childhood leukemia risk is potentially protective:  provides many immunological benefits to the offspring     antimicrobial immunoglobulins, lymphocytes, macrophages soluble factors  that may contribute to an altered response to infection  (Lightfoot and Roman, 2004). Childhood Cancers  IONIZING RADIATION Childhood  MATERNAL DIET Brain Tumors (cured meats)  PESTICIDES (paternal farm, forestry, residential)  SOLVENTS  HYDROCARBONS (fathers in the petroleum or chemical industries) Childhood Brain Tumors (CBT)  Brain tumors are the most common solid tumors in     children. The incidence of CBT increased by 29% between 1973 and 1994. Exposure to farm animals and pets have been considered possible risk factors (bacteria, pesticides, solvents and some animal oncogenic viruses). Maternal exposure to pigs has been associated with excess risk to primitive neuroectodermal tumors. Diets high in nitrosamines and low in specific vitamins provide some leads into the aetiology of CBT although much remains unknown  (Yeni-Komshian & Holly, 2000). Malignant neoplasms of the brain and central nervous system  second most common form of cancer in children (one sixth of their malignancies).  Recognized risk factors are   high doses of ionizing radiation from such sources as radiotherapy and atomic bomb exposure, certain inherited and genetic conditions.  Results from some studies suggest that parental occupational exposure to ionizing radiation and substances encountered in the petroleum, chemical, and paper industries may increase brain cancer risk in children (Kheifets, 2001).  Methodologies are inconsistent to draw conclusions and there is potential for biased data with reporting. Electric and Magnetic Field Exposure and Brain Cancer  hypothesized that EMF promotes the progression of cancer rather than initiating carcinogenesis.  Malignant gliomas: glioblastoma and astrocytoma  These brain tumors account for a large proportion of brain cancers in children.  Epidemiologic evidence is weak, but the studies are full of confounders. Bain Cancers in Adults  Adult brain cancers have been associated with organic solvents and pesticides and have been found in occupational groups including farmers, firefighters, and health professionals who use preservatives such as formaldehyde. Hormonal factors may be involved in the development of meningioma, a predominantly female tumor  (Kheifets, 2001). Childhood Cancers  Neuroblastoma  SOLVENTS (benzene, alcohols, lacquer thinner, turpentine, diesel fuel): paternal occupational  AROMATIC AND ALIPHATIC HYDROCARBONS: parental occupation Childhood Cancers Wilm’s  PESTICIDES Tumor Parental farm exposures  HYDROCARBONS  HAIR DYE  PARENTAL OCCUPATION (hairdressing, electronic, laboratory work) Childhood Cancers Hepatic  PARENTAL Tumors OCCUPATIONAL EXPOSURES (metals, petroleum products, paints, pigments) Childhood Cancers Germ Cell  PRENATAL Tumors RADIOGRAPHIC EXPOSURE  PARENTAL OCCUPATION (solvents) Childhood Cancers Retinoblastoma  PATERNAL OCCUPATION (military, metal manufacturing, welding) Childhood Cancers Malignant  RAD’N THERAPY   Bone Tumors   (for childhood cancers) ALKYLATING AGENTS RADIUM PESTICIDES PARENTAL OCCUPATION (chicken farming) Childhood Cancers Sympathetic  SMOKING AND Nervous System ALCOHOL (maternal)  PATERNAL OCCUPATIONAL EXPOSURES Agricultural, pesticides, hydrocarbons, rubber, paint, dusts, electrical components. Best Practices in Surveillance  Identify carcinogens  Monitor levels and possible health effects  Collect exposure information in a central database or registry  Inform workers or communities of the degree of their exposures  Take action to minimize or eliminate exposures to carcinogens Insert “In Harm’s Way” OH67