Page 62 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Concepts in Veterinary Toxicology Chapter | 1 29

VetBooks.ir tory levels, it is important to recognize that they are set to carcinogenic risks to humans are all available on line
In considering all of the foregoing guidance or regula-
(IARC, 2011). The monographs cover the carcinogen
control exposures for workers or the general public. In
classification reviews of nearly 1000 agents. It is ironic
each case, they are set to be health protective and, thus, that over the decades IARC has only classified one chem-
are set at levels below where human effects have been ical, caprolactan, used in the manufacture of nylon, as
observed or are expected to occur. These values should “unlikely to cause cancer in humans.” It has clearly been
not be interpreted as being equivalent to levels producing easier for scientists on IARC panels to address hazards in
adverse effects in humans. contrast to safety. This dichotomy needs to be addressed
since the public is interested in both. The NTP publishes,
on an irregular schedule, a Report on Carcinogens. The
Cancer as an Endpoint
14th Report was released in November 2016 (NTP,
For cancer as an endpoint, animal exposure response 2016). The total number of agents listed as “human carci-
studies may provide two kinds of input. First, the results nogens” or “reasonably anticipated to be human carcino-
may be used in Carcinogen Classification Processes such gens” to date is less than 300. The potency of the various
as those of the IARC, the EPA or NTP. As discussed ear- agents for causing cancer is quite varied. When examin-
lier, these are hazard-based classification schemes—a ing this literature, many in the public, including some
given agent capable of causing human cancer without scientists, are surprised to learn how few agents (less than
consideration of the potency of the agent. These schemes 100) have been conclusively identified as “human carci-
have been described elsewhere (McClellan, 1999, 2010; nogens.” These facts stand in sharp contrast to the view
McClellan et al., 2006). conveyed in the popular media and some scientific publi-
If a positive cancer outcome is observed in animal cations that people live in a “world of carcinogens.”
studies, the quantitative exposure-cancer response data
may be used in a second way: to develop a risk coeffi- New Potential Endpoints
cient, lifetime cancer risk per unit of exposure, describing
the potency of the agent for causing human cancer. Such In recent years, the expansion of knowledge at the molec-
extrapolations typically involve linear statistical extrapo- ular and cellular level has provided the opportunity for
lations from high levels of exposure used in the animal considering the addition of a myriad of new endpoints to
studies to potential human exposure levels several orders toxicological evaluations. This includes an array of new
of magnitude lower (recall Fig. 1.3). In addition, they molecular biomarkers that have received substantial atten-
may purposefully be calculated based on upper 95% con- tion. Although biomarkers are frequently discussed as
fidence limit on some level of risk, e.g., with a probability new approaches, it is well known to veterinary clinicians,
of a one in one million occurrence for environmental toxicologists, and to physicians that biomarkers have been
exposures or 1 in 10,000 for occupational exposures as used in both human and veterinary medicine for centuries.
discussed earlier. In my opinion, these extrapolated values In some cases, measurement of the biomarkers present
are highly uncertain. It is quite possible that for some in body fluids, urine, or exhaled breath, serve as an indi-
agents classified as possibly or probably carcinogenic to cator of exposure or, even, dose of a toxicant. Recall the
humans in the absence of a positive association with can- report of the individual arrested for “driving while intoxi-
cer from epidemiological studies and, thus, based on high cated” based on a breathalyzer test for exhaled alcohol
exposure level animal study results, there is no added can- that has been converted to a blood alcohol level. In other
cer risk at very low levels of exposure (Gold et al., 2003). cases, the biomarker is an indicator of a disease process.
The EPA (2005a) has issued guidance for alternative Recall individuals being evaluated for prostate cancer
approaches to estimate cancer risks when information is based on an elevated level of prostate specific antigen in
available on the mode of action of the agent, e.g., if the serum samples.
cancer arises as a result of the toxicity and secondary cell New biomarkers of exposure will continue to be pro-
proliferation rather than a direct effect of the chemical or posed. For each potential biomarker of exposure, it will
metabolite on DNA. For example, chloroform has been be necessary to conduct experiments to validate the utility
shown to cause cancer by this mode of action of the biomarker. A special challenge relates to recogniz-
(Butterworth et al., 1995). The EPA (2005b) has also pro- ing the dynamics of the toxicokinetics of various toxicants
vided guidance for considering the impact of susceptibil- and establishment of quantitative relationships between
ity of early life exposures for causing cancer. exposure and dose at any particular time over the course
Information on the cancer-causing potential of various of the intoxication.
chemicals is included in the material summarized in the The potential list of biomarkers for toxic responses is
USEPA’s Integrated Risk Information System (EPA/IRIS, seemingly endless. In all fields of medicine, from differ-
2011). The IARC monographs on the evaluation of ent kinds of cancer to various functional diseases of every