Cancer and the Environment Lecture Series

Cancer and the EnvironmentLecture Series

Alan Abelsohn MD FCFPRiina Bray MD CFPC

Ontario College of Family PhysiciansSupported by the

Saunders-Matthey Cancer Prevention Coalition

Outline

Breast Cancer OverviewCasePediatric 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


Patient Interest

Wendy Mesley. CBC Marketplace. March 2006

0 10 20 30 40 50 60 70 80 90 100

Netherlands

Denmark

Israel

Germany

Portugal

Mexico

Peru

India

Chad

Gambia

Breast Cancer Incidence Rates

Breast Cancer Rates Worldwide

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 Benzene Carbon tetrachloride Ethylene Oxide

Formaldehyde Lead oxide Methylene chloride Styrene

Refs: Blair and Kazerouni, Cancer Causes & Control, 8:473-490, 1997 Cantor et al., J. Occup. Environ. Med., 37:336-348, 1995Goldberg and Labreche, Occup. Environ. Med., 53:145-156, 1996Hansen, Am. J. Ind. Med., 36:43-47, 1999Norman et al., Int. J. Epidemiology, 24:276-284, 1995Spiritas 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

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

Types of compounds that cause mammary Types of compounds that cause mammary (breast) tumors in laboratory animals(breast) tumors in laboratory animals

Refs: Dunnick et al., Carcinogenesis, 16:173-170, 1995Refs: Dunnick et al., Carcinogenesis, 16:173-170, 1995Bennett and Davis, Environ. Mol. Mutagen. 39:150-157, 2002Bennett 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, 5:119-137, 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

Vulnerable periods in mammary development. Epidemiologic studies different ethnic groups of young girls life exposures to variety of environmental, nutritional and social factors that impact puberty.

www.bcerc.org/index.htm

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


Activist Ban “cosmetic” pesticide use local town council Quebec: first province to outlaw the cosmetic

use of pesticides Other municipal by-laws


CT Scan Abdomen

Non-Hodgkins LymphomaDiffuse Large Cell

Lymph node biopsy


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

Political action phase out cosmetic pesticide use

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; 111:377-382.


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)


Conclusion: “Organic diet reduced children's exposure levels from above to below US EPA guidelines”.

Childhood Cancers


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.

Insert “In Harm’s Way” OH16

KnownEffects

Under-recognition of Toxic Threats:Epistemological Bias

THE “UNKNOWN

UNKNOWN”

WHAT WE KNOW

WHAT WE DON’T KNOW

Thousands of chemicals

Billions of mixtures

Gene-environment interactions

Windows of vulnerability

Long latency effects

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 Myelogenous Leukemia (AML)

PESTICIDESpaternal occupation

SOLVENTSBenzene, alcohols, chorinated solvents in paternal occupation before, during and after

NITROGEN DIOXIDEpaternal before preg.

HYDROCARBONSmaternal during preg

Childhood Cancers

Acute Lymphocytic Leukemia (ALL)

SOLVENTS

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

Childhood Brain Tumors

IONIZING RADIATION MATERNAL DIET

(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 Tumor

PESTICIDES Parental farm exposures

HYDROCARBONS HAIR DYE PARENTAL

OCCUPATION (hairdressing, electronic, laboratory work)

Childhood Cancers

Hepatic Tumors

PARENTAL OCCUPATIONAL EXPOSURES

(metals, petroleum products, paints, pigments)

Childhood Cancers

Germ Cell Tumors

PRENATAL RADIOGRAPHIC EXPOSURE

PARENTAL OCCUPATION (solvents)

Childhood Cancers

Retinoblastoma PATERNAL OCCUPATION

(military, metal manufacturing, welding)

Childhood Cancers

Malignant Bone Tumors

RAD’N THERAPY

(for childhood cancers) ALKYLATING

AGENTS RADIUM PESTICIDES PARENTAL

OCCUPATION

(chicken farming)

Childhood Cancers

Sympathetic Nervous System

SMOKING AND 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” OH67PROVEN HARM

PARTIALLY PROVEN

NOT YET RECOGNIZED

FOREVER UNRECOGNIZED

THE TOXIC ICEBERG

Cancer and the Environment Lecture Series

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