Is the Human Carcinogen Arsenic Carcinogenic to Laboratory Animals?
TOXICOLOGICAL SCIENCES
Is the Human Carcinogen Arsenic Carcinogenic to Laboratory Animals?
James Huff 0
Po Chan 0
Abraham Nyska 0
0 Division of Intramural Research; National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina 27709
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Arsenic has long been known to cause cancer in humans
(Hutchinson, 1987, 1988), and has been correlated
convincingly with cancers of the skin, lung, liver, kidney, and urinary
bladder (IARC, 1987; NTP, 2000). Paradoxically, we now
know that arsenic has been shown to be anticarcinogenic as
well, and of potential benefit in the treatment of acute
promyelocytic leukemia (Zhu et al., 1999). Whereas this is a major
cancer chemotherapeutic advance, we believe use of arsenicals
in human medicine must be tempered by toxicological realities
(Huang et al., 1998; Huff et al., 1999). Nonetheless, most if not
all cancer chemotherapeutic agents are carcinogenic to
animals, and cause eventual second primaries in humans.
In summarizing the informative and valued proceedings
from a recent symposium on arsenic, Goering et al. (1999)
stated that animal carcinogenicity data for arsenic is
considered either negative or equivocal. These authors make a more
discerning statement two paragraphs later: Animal bioassays
are considered either flawed or incomplete for establishing
carcinogenicity of arsenic in rodents. They also contend that
the International Agency for Research on Cancer (IARC) has
determined that arsenic is the only agent to be a definitive
human carcinogen in the face of inadequate evidence of
carcinogenic potential in animals.
In fact, none of these statements is fully correct; the second
quoted sentence above comes close. In 1987 IARC evaluated
arsenic and arsenic compounds and concluded there is limited
evidence of carcinogenicity in experimental animals, meaning
there are tumor responses in some studies on arsenic
carcinogenicity in animals but due to certain deficiencies (too few
animals, low doses, short duration, no controls, arsenic
mixtures) the findings were not considered sufficient evidence of
carcinogenicity in animals. In these assorted and seemingly
numerous studies, various forms of inorganic arsenic were
associated with tumors of the lung, respiratory tract, and
stomach (IARC, 1980, 1987). Moreover, as we have stated
previ
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ously (Huff et al., 1998a,b), arsenic trioxide and other
inorganic (and until now organic) arsenicals have in reality never
been tested adequately for carcinogenesis, and never by the
inhalation route. Thus, to state that arsenic has not been shown
to cause cancer in laboratory animals is patently premature
(Chan and Huff, 1997). Unfortunately, a common and
perpetuated incorrect statement is often made that arsenic is
carcinogenic to humans and not to experimental animals. Bioassays
should be done, in particular with arsenic trioxide, to satisfy
this frequently but wrongly opined discrepancy.
As history often repeats, this reminds some of us of when
benzene was also heralded as being carcinogenic to humans but
not to animals, and the lack of carcinogenicity in animals for
both arsenic and benzene was used to discount the relevancy of
bioassay testing results for predicting human cancer risks. It is
now clear that, after adequate testing of benzene in animals, the
results have been overwhelmingly positive for carcinogenicity
(Huff et al., 1989; Maltoni et al., 1989). We believe the same
will occur if inorganic arsenic is tested properly in laboratory
animals.
In addition to arsenic, and contrary to the quoted comment
by Goering et al. (1999), other IARC Group-1 human
carcinogens have less than sufficient evidence of carcinogenicity in
animals, largely because only one study has been reported, and
in some cases there is no evidence at all because no bioassays
have been done. These substances are listed in Table 1. For
some of these there may be more recent experimental data that
we are either unaware or have been unable to locate. Despite
this collective observation, correlations between bioassays and
epidemiology findings are excellent (Huff, 1994, 1998, 1999a;
Tomatis et al., 1989; Wilbourn et al., 1986).
And of course, in addition to these 10, plus arsenic, one must
recognize that there are six mixtures, 13 industries or
occupations, as well as 10 biological agents or viruses (Table 2) that
are carcinogenic to humans, and that have not, and typically
cannot, be studied in animals. Granted, for many of these,
bioassays either cannot be done or can only be accomplished
with great difficulty, although particular agents within an
in
Chemicals Causing Cancer in Humans with Limited, Inadequate, or No Data of Carcinogenicity in Laboratory Animals
Agent(s) causing cancer in humans
dustry have been evaluated. For example, in the rubber
industry, benzene and 1,3-butadiene are both carcinogenic to
humans and animals.
Hence, 40 agents or expo (...truncated)