Page 45 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

12 SECTION | I General

VetBooks.ir stochastic approach to assess the health risks of using Tomatis, provided leadership for creating a program to
classify agents or occupations as to their carcinogenic
radiation devices in space and commercial nuclear power.
potential with the results published in a series of mono-
The probabilistic approach using the linear no threshold
exposure response model discussed earlier was conve- graphs (IARC, 1972); hence it is frequently referred to as
nient to use because it could be readily applied to asses- the monograph program. The view was that if cancer-
sing the risks to both individuals and populations. My causing chemicals or other agents, such as radiation, or
first experience with probabilistic risk assessment came in workplace conditions involving exposure to chemicals or
1965 when I was on a temporary assignment with what other agents causing cancer could be identified, then these
was then the US AEC. I worked with a joint AEC- could be controlled, perhaps even eliminated, and the
National Aeronautics and Space Administration Committee occurrence of cancer in people reduced. The IARC car-
assessing potential human cancer risks of accidents cinogen classification scheme considers human, labora-
involved with the launch of space craft containing pluto- tory animal, and supporting data to classify agents or
nium-238 fueled thermal electric power systems. workplace conditions as (1) carcinogenic to humans,
Another factor influencing public concern was the (2) probably carcinogenic to humans, (3) possibly carci-
increasing incidence of total cancers being observed in all nogenic to humans, (4) not likely to be carcinogenic to
of the economically developed countries, including the humans, or (5) not classified as to carcinogenicity. It is
United States, that were driven largely by lung cancer. It important to recognize that the IARC classification is
is now well known that the increase in lung cancer, first strictly hazard-oriented. It does not formally evaluate the
observed in men and later in women, was largely related potency of these agents for causing cancer at a specific
to cigarette smoking. The different pattern in men and level of exposure.
women relates to a large increase in men smoking earlier The USEPA, the NTP, and other organizations have
than women. Many women began smoking during World developed similar carcinogen classification schemes
War II. Rachel Carson’s book also created concern for (EPA, 1986, 2005a,b; NTP, 2005). The EPA cancer haz-
exposure to man-made chemicals contributing to the ard scheme is virtually identical to that of IARC.
increasing incidence of cancer and encouraged the view However the NTP scheme differs in that it classifies
that somehow man-made chemicals were different than agents as (1) human carcinogens or (2) reasonably antici-
chemicals of natural origin. It is now known that this is pated to be human carcinogens. In recent years, IARC
not the case (Gold et al., 2003). Ironically, some major (1991) has made provision for increased use of mechanis-
commodity chemicals such as formaldehyde are normal tic data in classifying chemicals as human carcinogens.
constituents of mammals were related to the one-carbon Both the EPA and NTP now also give increased emphasis
metabolic cycle (Golden, 2011). to the use of mechanistic data in classifying chemicals as
The experience with radiation soon resulted in its use carcinogens (EPA, 2005a,b) unlike IARC and the NTP,
as a proto-typical carcinogen in developing approaches to the EPA does develop estimates of cancer-causing
risk analysis and risk regulation. Albert (1994) documen- potency for some agents classified as having cancer-
ted the development of the USEPA’s approach to asses- causing potential. This, in turn, using measurements or
sing cancer risks. Key assumptions in the approach were: estimates of exposure, provides the basis for calculating
(1) cancer-causing chemical agents acted like radiation in lifetime cancer risks for individuals or populations.
causing cancer; (2) there was a linear relationship It should be apparent that the classification of a given
between exposure (dose) and increased risk of cancer chemical or agent as to its cancer-causing potential is
extending to the lowest levels of exposure; (3) agents insufficient for characterizing cancer risk since the
causing cancer in laboratory animals could be viewed as hazard-based classification does not include an estimate
also causing cancer in people; and (4) exposure response of the agent’s potency. The USEPA has estimated the car-
relationships could be extrapolated between species by cinogenic potency for a number of chemicals. The results
considering differences in body weight and surface area, are usually related as the concentration of a chemical in
i.e., metabolic activity. These assumptions were viewed water or air that will result in a calculated one in a million
as default options to be used in the absence of specific probability of cancer occurring above the background
scientific data to the contrary (McClellan, 1994, 1999, incidence (EPA/IRIS, 2011). In viewing such estimates it
2003; NRC, 1994). is useful to recall that in developed countries of the world
In response to public concern for chemicals causing with long-lived populations, about one-third of the popu-
cancer, the International Agency for Research on Cancer lation will be diagnosed with cancer during their lifetime
(IARC), a part of the World Health Organization, was and one-fourth will die with a cancer. Cancers are a large
organized in Lyon, France, in 1965 under the leadership family of related diseases that do occur frequently, espe-
of John Higginson to develop an international research cially in aged populations. To estimate the cancer risk for
program to study cancer. Higginson’s deputy, Lorenzo any agent and exposure situation, it is also necessary to