Page 47 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

14 SECTION | I General

VetBooks.ir the Lovelace Institute with rats exposed to low dilutions (as independent evaluation of the evidence, which concluded
The Health Effects Institute sponsored a study at
there were serious shortcomings in the IARC evaluation.
The results of the independent evaluations have been pub-
low as 20 to 1) of exhaust from a 2007 EPA-compliant
engine fueled with ultra-low sulfur fuel. The highest lished in a special Supplement to Critical Reviews
exposures were less than 1% of the particle matter concen- in Toxicology with a commentary I prepared as editor of
trations studied earlier using traditional diesel technology the journal (McClellan, 2016a,b; Williams et al., 2016a,b;
engines. In contrast to the findings observed earlier with the Solomon, 2016; Brusick et al., 2016; Acquavella et al.,
traditional diesel engines, an excess of lung cancer was not 2016). I encourage individuals to read both the original
observed (Mauderly et al., 1987; McDonald et al., 2015). IARC report and the reports prepared by the reevaluation
Almost concurrently, results were published by team to gain an appreciation of the complexities of
NIOSH and NCI investigators on a large Diesel Exhaust the IARC cancer hazard classification process and the
in Miners Study (DEMS) (Attfield et al., 2012; Silverman uncertainties associated with evaluating the carcinogenic
et al., 2012). The DEMS involved 12,315 workers from hazard of a single, well-studied chemical such as glypho-
eight nonmetal mines (three potash, three trona, one salt, sate. This will also give the reader an appreciation of the
and one limestone) whose exposures and vital data were role of both epidemiological and animal evidence in the
assessed through 1997. Thus, these exposures were from cancer-hazard classification process.
emissions from traditional technology diesel engines. The Increasingly, the “precautionary principle” has dominated
initial reports by the NIOSH/NCI investigators revealed a approaches to regulation of products and technologies. The
positive association between respirable elemental carbon concept took hold first within Europe and was codified by
exposure (extrapolated from CO measurements) and the European Commission (2002), more recently its use has
excess lung cancer. These findings were instrumental in been advocated in the United States. In its most simple form
an IARC (2012) panel upgrading the classification of die- it argues that if the product or technology has not or cannot
sel exhaust exposure from a probable human carcinogen be viewed as safe then the product or technology should be
to a human carcinogen. Later, the HEI evaluated the most replaced or not used. It is obvious that the “devil is in the
recent epidemiological findings, including the DEMS details” with regard to the basis for characterizing what is
results and concluded that the findings could be used for safe or not safe. There is a continuum from safe products or
quantitative risk assessment in addition to their use in technologies to highly hazardous products and technologies.
cancer hazard classification (HEI, 2015). Indeed, some highly hazardous products may be used in a
More recently, a team I have been associated with controlled manner so they do not pose a significant health
gained access to the DEMS data, replicated the original risk. Some advocates of the “precautionary principle” point
analyses and then extended the analyses. The use of alter- to thousands of untested chemicals and argue they should be
native exposure assessments, which were viewed as being tested or banned. I would argue that a critical review of past
equal to or superior to the original DEMS estimates, experience with many of these chemicals or closely related
yielded substantially reduced lung cancer hazard esti- chemicals provides a sound basis for their continued use.
mates. When radon was included in the analyses the haz- Quite frankly, additional extensive testing using laboratory
ard estimates were further reduced and generally no animals may not be warranted. Moreover, I am concerned
longer statistically significant (Moolgavkar et al., 2015; that many of the in vitro cellular and molecular assays have
Crump et al., 2015, 2016). These findings emphasize that not yet been appropriately validated as predictors of the pres-
a high degree of caution should be exercised in extrapo- ence or absence of adverse health effects in humans.
lating the DEMS findings selectively or in toto to other The “precautionary principle” is a core element of the
populations or in using them for quantitative risk assess- Registration, Evaluation, Authorization, and Restriction
ment. This body of work emphasizes the importance of of Chemicals (REACH) program established by the
important epidemiological data sets being made available European Commission (2006). More details are available
for analysis by multiple investigators, especially when the at REACH (2011). Thoughtful reviews of the REACH
results have public policy impact. The same applies to program have been written by deAvila and Sandberg
large data sets assembled in studies by veterinary toxicol- (2006) and Williams et al. (2009).
ogists of animal populations. Such use should be part of Potential changes in how chemicals are regulated in
the planning process when the study is designed. the United States have been debated for decades. That
A recent IARC monograph program decision of spe- debate resulted in passage in 2016 of the Frank R.
cial interest to those of us interested in agricultural and Lautenberg Chemical Safety for the 21st century Act
food production issues concerns the widely used herbi- amendments to the Toxic Substances Control Act signed
cide, glyphosate, frequently marketed as Roundup. IARC by the President of the United States on June 22, 2016
(2015) evaluated the epidemiological, animal, and sup- (TSCA, 2016). These amendments establish mandatory
porting evidence on glyphosate and classified it as requirements for the USEPA to evaluate existing chemi-
a probable human carcinogen. This action prompted an cals, have all new chemicals evaluated before commercial