Page 46 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Concepts in Veterinary Toxicology Chapter | 1 13

VetBooks.ir estimate the exposure to the agent, both as to intensity, classification scheme used by IARC. One area of contro-
Controversy continues over the carcinogen hazard
i.e., concentration and duration. In short, risk is a product
of exposure and the potency of the agent for causing
versy concerns evaluating cancer hazards related to tech-
the effect. Paustenbach (2001) provides an excellent nologies, especially to technologies whose emissions may
review of the practice of exposure assessment. change over time. A specific chemical such as benzene
There has been a tendency for regulatory agencies, such remains constant over time with a continual increase in
as the USEPA, to use their experience with classifying the knowledge that will inform the cancer hazard classifi-
chemicals as to their carcinogenic potential as a template for cation process. Benzene studied in 2017 is the same mole-
also classifying chemicals as to their potential for producing cule as was studied at earlier times. The situation may be
other noncancer hazards. Thus, there has been a trend for different specific technologies that are constantly
toward classifying chemicals as to their potential hazard for changing, sometimes with changes to reduce emissions.
causing different health outcomes and labeling them as An excellent example is the diesel engine, the compression
such, i.e., neurotoxins, reproductive toxins, hepatic toxins, ignition engine using liquid hydrocarbon fuel invented by
etc. Indeed, some even broader classifications have Rudolph Diesel in the 1890s (McClellan et al., 2012). The
emerged, i.e., endocrine-disrupting chemicals. In my view, utility and efficiency of diesel engines resulted in their rapid
this shorthand approach to identifying and classifying deployment and use in many applications. A pre World War
hazardous agents as to their potential to cause cancer or II concern for diesel exhaust emissions focused on their odor
other effects is often confusing to the public. In my opinion, and impact on visibility. Demonstrations in the 1970s that
the labeling approach has contributed to both radiation extract of diesel exhaust particles painted on mouse skin
phobia and chemical phobia and sometimes irrational caused cancer and were mutagenic in the newly developed
actions. It certainly flies in the face of the fact that for many Ames assay raised concern for inhalation exposure of diesel
chemicals the admonishment of Paracelsus that “the dose exhaust potentially causing lung cancer. These concerns stimu-
makes the poison” remains true. For numerous chemicals, lated research using multiple approaches. A number of
even when toxic effects are apparent at high doses, these epidemiological studies yielded results suggesting that expo-
same adverse effects are no longer manifest at sufficiently sure to exhaust from diesel engines in use in the 1950s and
low doses. Gold et al. (2003) has discussed the challenge of 1960s caused an increase in lung cancer. Four different labora-
using high-exposure (dose) animal studies to identify either tories in the United States, Germany, Switzerland, and Japan
man-made or natural chemicals as human carcinogens. reported that long-term exposure to high concentrations of
In recent years increasing attention has been given to diesel exhaust particulate material caused an increase in lung
developing safer products and technologies, especially when cancer in rats (Hesterberg et al., 2005, 2011; McClellan et al.,
concerns have been raised with regard to the hazards of an 2012). Mauderly et al. (1987) is an example of one of those
existing product or technology. In some cases, the focus has studies of traditional diesel exhaust. An IARC (1989) panel on
been on developing products that do not have carcinogenic which I served evaluated the evidence and classified exposure
properties to replace products that have been classified as to diesel exhaust as a probable human carcinogen. Soon new
human carcinogens or probable or possible human carcino- research provided evidence that the increase in lung cancer in
gens by IARC or as known or reasonably anticipated to be rats to high concentrations of exhaust particles for long periods
human carcinogens in the Report on Carcinogens periodi- of time involved a nonspecific overload phenomena suggest-
cally prepared by the NTP. Endpoints other than cancer have ing that the effects observed in rats were not relevant for
increasingly drawn attention for chemicals such as Bisphenol evaluating human hazards/risks at low levels of exposure
A, which has been under attack as an endocrine-disrupting (Wolff et al., 1987; Nikula et al., 1995). Nikula et al. (1995)
chemical. A committee of the National Academies of showed that chronic exposure of rats to high concentrations of
Science, Engineering and Medicine chaired by a Veterinary carbon black particles free of hydrocarbons produced an
Toxicologist, David Dorman, has recently released a report increase in lung cancer.
(NASEM, 2017) that will guide future assessments of what it In response to the 1988 IARC hazard classification, a
calls endocrine active chemicals. In general, chemicals that related evaluation by the NTP, and an independent hazard
persist in the environment and have a long residence time in evaluation by the USEPA, the EPA issued stringent emis-
animals and humans, even when shown to have low hazard sion standards for particulate matter and NO 2 emissions
potential, have become targets for replacement. In yet other from diesel engines and mandated the use of ultra-low
cases, the approach has been to identify replacements for sulfur fuel (less than 15 ppm) for on-road vehicles.
chemicals that are persistent in the environment and have Industry responded with advances in engine technology,
long residence time in animals and humans. In other cases, exhaust after-treatment, and electronic control systems
the approach has been to find ways to minimize the use of that, along with use of ultra-low sulfur fuel, met the strin-
the chemical viewed as being unsafe. These activities have gent particulate matter emission standards in 2007 and
givenrisetoafieldofscience sometimesreferredtoas also stringent NO 2 emission standards in 2010 (McClellan
“green chemistry” (Anastas and Warner, 1998). et al., 2012).