Society of Toxicology
Carcinogenesis Specialty Section (CSS)
Winter 2004 Newsletter
KEY DATES
March 22 – CSS Officers Breakfast Meeting at Renaissance
Harborplace Hotel – Window’s Restaurant (7 – 8:30 AM)
March 22 – CSS Meeting – Baltimore Convention Center,
Room 325 (6 - 7:30 PM)
April 30 – CSS-sponsored programs due to SOT
Headquarters
PRESIDENT’S MESSAGE:
Dear Specialty Section Members:
It’s that time of year again!! I hope you will join us at the CSS meeting,
which will be on Monday evening. We are going to present the Best Paper
Awards (See Below) and introduce our new CSS Officers (See Below). In
addition, we will discuss the results of the CSS survey and hand out CSS
Mugs to those that filled out the survey. So please come by and meet old
friends and make new ones.
I want to thank Dr. Marie-Elise Parent for writing our guest article entitled
Epidemiological Evidence For A Role Of Environmental Chemicals In
Prostate Cancer Development. Dr. Parent is at the INRS-Institut ArmandFrappier, Université du Québec, Laval, Quebec, Canada. I hope you enjoy the article!!
At this annual meeting, the CSS is organizing the following programs:
 A continuing education course entitled “Adrenal Gland: Mechanisms of Toxicity
and Carcinogenicity” which is chaired by Jon C. Cook.
 A symposium entitled “Biomarkers: Development, Evaluation, and Use” which is
co-chaired by Ruth A. Roberts and Tom Monticello.
The CSS is co-sponsoring the following symposia and workshops:
 Arsenic Disruption Of Cell Cycle: Mechanisms and Effects on Apoptosis,
Differentiation And Carcinogenesis
 Xenobiotic-Activated Receptors: Biological Functions and Disease Prevention
 The Present and Future of Toxicogenomics in Preclinical Drug Development
 Toxicogenomic Databases and Their Role in the Toxicology Community
 Molecular Profiling and Computer Modeling in Early Detection and Treatment of
Cancer
 Nutraceuticals as Double-Edged Swords: Weighing Benefits and Risks of Dietary
Chemicals to Human Health
I encourage you to support these programs by your attendance. If you have program
ideas for the 2005 annual meetings please bring these to the meeting and discuss them
with the CSS Officers.
Sincerely,
Jon C. Cook
President
CONGRATULATIONS TO 2004 STUDENT AWARD WINNERS:
The 2004 CSS graduate student or postdoctoral fellowship
poster prize competition was a huge success with 12 entries, all of
an impressive standard. Entries were judged on scientific merit,
clarity of presentation and relevance to toxicology and
carcinogenesis. The CSS officers had a difficult but enjoyable
task finding the winners, but in the end First Prize in the graduate
student competition went to Leanne Bedard of Queen’s
University, Kingston, Canada for her poster entitled ‘Differences in
DNA repair activity and inhibition of repair by Aflatoxin B1 correlates with susceptibility
to carcinogenesis in mouse’. Second and third places went to Ammie Carnell (Michigan
State University) and Cécile Michel (Aventis Drug Safety Evaluation, Paris, France),
respectively. First Prize in the postdoctoral fellowship competition went to Dr Jingbo Pi
of the Laboratory of Comparative Carcinogenesis, NIEHS for his poster entitled
‘Arsenic-induced transformation causes generalised resistance to apoptosis in cultured
human keratinocytes’. Honorable mention certificates will also be given to the other
students who participated in the competition.
All award winners will be presented with a plaque or certificate together with a monetary
prize ($500, $300 or $100) at the CSS meeting (SOT, Baltimore). In addition, Leanne
Bedard will participate in the 2004 SOT CSS officers meeting as student representative.
This annual competition is a great opportunity for our students and postdocs to publicise
their hard work so please spread the word and encourage even more of them to enter in
2005. The CSS officers would like to thank all entrants and their supervisors for taking
part in the competition and many congratulations to the winners!
ENCOURAGE YOUR STUDENTS TO JOIN CSS:
Advisors, please encourage you students to joint the CSS. It is a
great way to network and to have the opportunity to serve as a
Student Officer of the CSS.
2004-2005 CSS OFFICERS
President - Ruth A. Roberts
Vice-President - John (Jef) French
Vice-President Elect - Michael L. Cunningham
Past President - Jon C. Cook
Secretary/Treasurer - Kyle L. Kolaja (May 2005)
Councilors - Richard J. Bull (May 2005),
Michel Charbonneau (May 2005), and
Lisa M. Kamendulis (May 2006)
Student Officer - Leanne Bedard
SUBMIT ARTICLES AND CSS MEMBER NEWS FOR THE CSS NEWSLETTER:
Please send Kyle L. Kolaja articles and member information for
inclusion in the CSS newsletters (kkolaja@iconixpharm.com) or by
phone (650-567-5554). Your continued support will ensure that this
remains an excellent specialty section.
Invited Article by Marie-Elise Parent – SOT Carcinogenesis
Epidemiological Evidence For A Role Of Environmental Chemicals
In Prostate Cancer Development
By Marie-Elise Parent, Ph.D., Assistant Professor,
INRS-Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada
Background
Prostate cancer is the most frequently occurring cancer among Canadian and American
men. Despite its favorable survival, there is significant morbidity associated with prostate
cancer and its treatment, with side effects seriously impairing the quality of life,
including permanent sexual impotence, urinary incontinence, anxiety, depression, hot
flushes, and osteoporosis (1,2). These unfavorable effects following prostate cancer
diagnosis clearly highlight the need to find ways to prevent this disease through the
identification of modifiable risk factors.
Efforts to elucidate the risk factors for prostate cancer have surprizingly met little success
to date. All that is known with certainty is that incidence increases exponentially with
age, is higher among men whose father or brother had the disease, and varies by
geography and ethnicity (3). Mortality rates for prostate cancer vary markedly between
countries. Migrant studies indicate that incidence increases among men who move from
low- to high-risk countries. Second- and third-generation migrants acquire levels of risk
that resemble those of their adoptive countries (4,5). These observations provide
compelling evidence that the etiology of prostate cancer involves environmental
influences and that this research area needs to be further explored.
Hormones are believed to contribute to the development of prostate cancer although their
precise role is not well understood (6). The normal function of the prostate is controlled
by testosterone, and androgenic stimulation of the prostate over a prolonged period may
promote or initiate carcinogenesis (5,7-9). The biological mechanism underlying many of
the suspected risk factors for prostate cancer is thought to be androgenic stimulation. The
prostate gland is also sensitive to estrogens (10). Administration of estrogens reduces
testosterone production, and is used to control disseminated prostate cancer. However,
there is epidemiologic and experimental evidence suggesting that estrogenic hormones
may cause DNA damage and thus initiate prostate cancer (6,11). These conflicting
observations may be explained by the fact that there are two distinct estrogen receptors,
ER and ER, which may have opposing roles. Taken together, these observations
suggest that both androgens and estrogens may influence the risk of prostate cancer.
Consequently, environmental factors which may modify either types of hormones may be
relevant to prostate cancer development.
Occupational and environmental chemicals
Investigating prostate cancer risks in relation to occupational exposures is important
because exposure levels in the workplace may be higher than in the general environment
and because most workplace substances find their way into the general environment in
one form or another (12). Understanding whether occupational chemicals cause prostate
cancer is important not only for prevention, but also for improving our knowledge of the
etiology of the disease. While there is still limited physiologic evidence on the extent to
which different exogenous chemicals may affect the prostate gland, it is known that
certain chemicals (i.e., dioxins, diesel emissions, etc.) can alter enzymatic activity in the
prostate (13,14). Furthermore, animal experiments have shown that prostate tumors can
be induced by the administration of certain chemicals such as cadmium (15).
A great deal of interest is being directed towards the hypothesis that certain
environmental chemicals may act as endocrine disruptors or modulators (5,7,10,16,17).
The endocrine effects are believed to be due to their ability to a) mimic endogenous
hormones such as estrogens and androgens, b) antagonize endogenous hormones, c) alter
the pattern of synthesis and metabolism of hormones, and/or d) modify hormone
receptors levels. As hormonal influences are likely related to the etiology of prostate
cancer, exogenous chemicals that can modulate the hormonal milieu are of particular
interest.
Several industrial chemicals have been associated with endocrine-disrupting effects
(16,18-22). These include some metals (cadmium, lead, mercury, aluminum), phenolic
derivatives (phenol, bisphenol-A, pentachlorophenol, resorcinol, PCBs), phthalates (used
as plasticizers), variously substituted benzenes (polycyclic aromatic hydrocarbons,
benzo[a]pyrene), styrenes (used in the manufacture of plastics and rubber), carbon
disulphide (used in the production of rayon), dioxin, and several organochlorine
pesticides, fungicides and herbicides. The halogenated aromatic hydrocarbons may
function as hormonal mimics and their resistance to metabolism and elimination is
generally much greater than for natural hormones. It is unclear whether exposure to
exogenous hormone modulators, which are much less potent than naturally occurring
endogenous hormones, can have adverse health effects (22). Extremely low exposures to
some endocrine modulators (plasticizers, alkylphenols) have been found to induce
adverse effects on the male reproductive tract of rodents (22). Significant concentrations
of chlorinated hydrocarbons can accumulate in the male genital tract, in the reception
zone for spermatozoa (23). Also, normal endogenous estrogens are bound to SHBG while
many exogenous estrogens are not and this may result in higher concentrations of free
compounds, which could then interact with estrogen receptors in the prostate (17).
In light of the suspected role of exogenous factors in the etiology of prostate cancer, the
search for evidence from the work environment has intensified. We were recently invited
to review the evidence regarding the possible etiologic role of occupation and
occupational exposures in prostate cancer (24). A number of occupations and
occupational agents to be discussed in the next paragraphs have come under suspicion,
notably: pesticides and other farming-related exposures, cadmium, metal-working
exposures and polycyclic aromatic hydrocarbons (PAH).
Farming, pesticides and herbicides: Several epidemiologic studies and broad
occupational surveys have examined the relationship between farming and prostate
cancer (10,25-42). As a whole, results from these studies are consistent with a weak,
positive association (25-27). The ostensible slight excess of prostate cancer contrasts with
low risks for most other cancers and nonneoplastic diseases among farmers (25). The
interpretation of this body of evidence remains uncertain (43). The positive associations
could reflect lifestyle factors or they could be the result of chemical exposures, or both.
Farmers’ activities encompass a wide variety of tasks, entailing potential exposure to
solvents, fuels and oils, metal dusts, welding fumes, engine exhausts, paints, various
organic and inorganic dusts, pesticides (which include insecticides), herbicides,
fungicides, zoonotic viruses, microbes, fungi, and sunlight (28).
Use of pesticides among farmers has been associated with prostate cancer in some (4449) but not all studies (50-52). We reported a statistically significant, two-fold excess risk
of prostate cancer among farmers exposed to substantial levels of pesticides (mainly DDT
and arsenic-containing pesticides), as compared to unexposed farmers (53); Risk
increased with higher frequency and duration of exposure. In the large on-going USbased Agricultural Health Study (48), exposure to chlorinated pesticides among
applicators and methyl bromide users was associated with prostate cancer risk. Italian
farmers exposed to organochlorine insecticides and acaricides, such as DDT and dicifol,
were also found at excess risks of prostate cancer (49). Nevertheless, discordant evidence
concerning hazards due to pesticides also comes from studies of workers involved in
manufacturing or spraying of these compounds (54-61). Likewise, among pesticide
applicators the evidence is conflicting (10,62-72). Most of these studies were quite small.
Several of the pesticides are estrogen-like compounds that can modulate hormone levels
(17). Finally, in a few studies (73,74), but not all (45,47,51,75), elevated risks for workers
exposed to fertilizers have been reported.
Cadmium: Cadmium is found in some insecticides and fertilizers, and exposure
can occur in several workplaces such as those of smelters, nickel-cadmium battery
operations, mines, metal construction sites, rubber production, and is used in paints and
plastics production; other sources include diet and tobacco smoke (30). Following some
early reports of excess risk of prostate cancer among cadmium-exposed workers, mainly
in battery production or smelting operations, more recent and larger studies failed to
confirm these (76). Although the cumulative epidemiologic evidence does not support the
cadmium-prostate cancer hypothesis (77), experimental data suggest that prostatic tumors
can be induced experimentally in rodents by oral exposure to cadmium (78). These
experiments demonstrated that the accumulation of cadmium in the prostate and the
induction of prostatic cancer by cadmium were androgen-dependent. It has also been
shown that cadmium can impair cell-mediated immunity, phagocytosis and natural killer
cell activity (79).
Metalworking-related exposures: There is some evidence that metal workers such
as mechanics, repairmen, and machine operators may be at increased risk of prostate
cancer (80-82). These groups of workers experience a large variety of complex
exposures., . Among the few studies were specific exposures examined , there was some
evidence of associations with some metallic dusts and with metalworking chemicals, such
as solvents, cutting oils, mineral oils, heating oils, hydraulic fluids, lubricating oils and
acids (80,83). However, another group which reviewed the available evidence on the risk
of prostate cancer among workers exposed to metalworking fluids considered it equivocal
(84).
Polycyclic aromatic hydrocarbons (PAH) and engine emissions: There is some
indication of excess risk in occupational groups with potential exposure to PAHs
(30,33,34,83,85,86). In the few studies that entailed substance-based exposure assessment
protocols, Aronson et al. (83) found excess risk in relation to liquid fuel combustion
products and PAH as a class (using expert-based exposure assessment) and Seidler (87)
found excess risk in relation to diesel fuel and fumes, soot, tar and pitch (using job
exposures matrices). It has been reported that diesel engine emissions induce changes in
enzymatic activities in the prostate glands of animals (14,87). In addition, the antiestrogenic effects of certain hydrocarbons, such as benzo(a)pyrene, may promote the
growth of prostate cancer cells. Several PAHs may interact, positively or negatively, with
estrogen receptor signaling (88).
Limitations of the available evidence on occupational factors: The vast majority
of studies of occupational circumstances and prostate cancer conducted to date were
retrospective mortality studies in which job or industry titles as recorded on death
certificates were used as indices of exposure. Such studies are useful in providing leads
and the evidence heretofore accumulated is certainly sufficient to warrant a deeper
exploration of the role of occupational factors in the etiology of prostate cancer.
However, little progress can be made through further studies of occupational titles and
prostate cancer; what is really needed are studies of occupational factors based on refined
exposure assessment protocols (12,43).
Probably one of the most detailed and in-depth evaluations of the association between
occupational exposures and prostate cancer has been carried out by our research group
through analyses of our multiple-site, case-control study conducted in Montreal in the
late 1970s (89,90). Several occupational substances exhibited moderately strong
associations with prostate cancer, including metallic dust, liquid fuel combustion
products, lubricating oils and greases, and polycyclic aromatic hydrocarbons from coal
(83). To our knowledge, this study is the only one to date providing an estimate of the
proportion of prostate cancer cases in the population that would be attributable to
occupational exposures. Our estimates of the etiologic fraction of prostate cancer due to
occupational chemicals ranged from 12 to 21%. While these estimates were imprecise
and possibly overestimated they nevertheless imply that occupational causes of prostate
cancer may be an important public health issue. Interestingly, we have recently found a
similar pattern of risk in relation to prostate cancer for exposure to some of these
substances during leisure-time activities (91).
Gene-environment interactions
The study of joint effects of genetic factors and environmental factors is a cutting-edge
issue in cancer epidemiology and may pave the way to significant advances in
understanding the etiology of prostate cancer (12). It is hypothesized that carcinogenmetabolizing genes may influence prostate cancer risks among individuals exposed to
exogenous chemicals. Many chemical carcinogens are not active by themselves and
require bio-activation by different enzymes (92,93). Genetic polymorphisms of
carcinogen-metabolizing enzymes could therefore play an important role in chemicallyinduced carcinogenesis. Several studies suggest that polymorphisms, such as gluthathione
S-transferases (GSTs) and N-acetyltransferases (NATs), may influence prostate cancer
susceptibility (94-101). Because of the relatively high frequency of some NAT1 and
NAT2 genotypes in the population, the attributable cancer risk may be high. The relative
risk associated with these two genotypes seems to be particularly high among subjects
exposed to aromatic and heterocyclic amines (94), either in the workplace or through
cigarette smoke. CYP1A1 which is particularly important for the metabolism of
polycyclic aromatic hydrocarbons, benzo(a)pyrene, PCBs and dioxin (92,93,102) and has
been reported to be associated with prostate cancer risk (98).
Conclusion
The descriptive epidemiology of prostate cancer points to the environment as one of most
promising research area to elucidate potential risk factors for this disease. There is some
suggestive evidence, albeit weak, that workplace chemicals, mainly farming-related
exposures, metal-working related substances, PAHs and combustion products, and
industrial hormone disruptors may be related to prostate cancer development. The
prevalence of several of these exposures being low, the statistical power for most studies
conducted to date on this subject would have been hard-pressed to detect associations.
Moreover, there is a dire need for more epidemiologic studies based on a detailed
exposure assessment scheme. The traditional approach of confirming hypotheses in
occupational cancer epidemiology, namely through cohort studies, would only allow for
one or a handful of these associations to be evaluated at a time. Only a population-based
case-control approach allows for the simultaneous assessment of many exposures. In this
context, in order to provide much needed evidence on the role of environmental,
occupational and genetic factors in prostate cancer etiology, we have recently undertaken
a large population-based case-control study at INRS-Institut Armand-Frappier. Results
from this study should be available in about four years.
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