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The Office of Environmental Health Hazard Assessment (OEHHA)
received a
request from Mr. Gary Roberts on April 5, 2002 that the statin
drugs all be reviewed for possible Proposition 65 listing by the
Carcinogen Identification Committee (CIC) at the same time.
The statins are a class of lipid-lowering drugs. All statin drugs
inhibit the enzyme 3-hydroxy-3-methylgluatryl-coenzymeA (HMG-CoA)
reductase. HMG-CoA reductase catalyzes the conversion of hydroxymethylglutaryl-CoA
to mevalonic acid, an early rate-limiting step in cholesterol
biosynthesis. In clinical studies, statins reduce total cholesterol,
LDL cholesterol, apolipoprotein B and triglyceride levels. Statins
increase HDL levels. The normal treatment regimen for these drugs
involves daily exposure over a period of many years.
Six drugs in the "statin" class have been marketed
for their hypolipidemic effects (see Figure 1): atorvastatin calcium
(LIPITOR), cerivastatin sodium (BAYCOL), fluvastatin sodium (LESCOL),
lovastatin (MEVACOR), pravastatin sodium (PRAVACHOL), and simvastatin
(ZOCOR). Cerivastatin sodium was withdrawn from the U.S. market
by the manufacturer in August 2001 because of reports of fatal
rhabdomyolysis (disintegration of muscle tissue). All statins
have been associated with rhabdomylosis, but severe cases have
been reported more frequently with cerivastatin sodium.
Figure 1. Structures of statin drugs
Lovastatin
 Simvastatin
 Pravastatin
sodium
 Fluvastatin
sodium
 Atorvastatin
calcium
 Cerivastatin
sodium
The prioritization
process usually involves random selection of chemicals being
tracked (OEHHA, 1997). Currently, only one of the six statin drugs,
lovastatin, has been prioritized and randomly selected (in February
1999) for consideration by the CIC for listing under Proposition
65. The other statin drugs are being tracked as a group, but have
not been randomly selected for prioritization as to carcinogenicity
concern. As stated in the prioritization process document, "(u)nder
exceptional circumstances, the process may be abbreviated to allow
OEHHA to respond to specific public health needs. Following consultation
with the Committee Chair, the Director of OEHHA may request that
a chemical be placed on the agenda of the next scheduled meeting."
In consideration of Mr. Roberts' request and consistent with the
prioritization process, the Director of OEHHA in consultation
with the Chair of the CIC included on the agenda the request for
discussion at the December 17, 2002 meeting.
As noted in the U.S. Food and Drug Administration's approved
package inserts for these six statin drugs, long-term administration
of the individual statins to experimental animals has been associated
with the induction of tumors at various sites. Information on
tumor induction is outlined in Table 1.
Table 1. Reported carcinogenicity of statin drugs, by tumor site
-
Liver
-
atorvastatin calcium (carcinoma, female
mice; adenoma, male mice)
-
cerivastatin sodium (carcinoma, male mice;
adenoma, male and female mice)
-
lovastatin (carcinoma, male and female mice;
male rats)
-
pravastatin sodium (carcinoma, male rats)
-
simvastatin (carcinoma, mice and rats of
both sexes)
-
Thyroid
-
simvastatin (adenoma, female rats)
-
fluvastatin sodium (adenoma and carcinoma,
male rats)
-
Lung
-
lovastatin (adenoma, female mice)
-
simvastatin (adenoma, male and female mice)
-
Forestomach
-
lovastatin (papilloma, female mice)
-
fluvastatin sodium (papilloma, male and
female mice)
-
Harderian gland
-
Muscle
Five of the statins induced tumors of the liver in rodents, and
tumors of the thyroid, lung and forestomach have each been induced
by one or more statins. The frequent concordance in tumor sites
between rats and mice (Table 1) and structural (Figure 1), pharmacologic
and toxicologic similarities suggest that a common mechanism of
action is involved in at least some of the carcinogenic effects.
The preparation of a cancer hazard identification document on
one statin (e.g., lovastatin) would necessarily entail a review
of the information available on the other statins. At the request
of the CIC, OEHHA can prepare a single document that comprehensively
presents the evidence of carcinogenicity for each of the statin
drugs.
References
Office of Environmental Health Hazard Assessment (OEHHA, 1997).
Procedure for
Prioritizing Candidate Chemicals for Consideration Under Proposition
65 by the "State's Qualified Experts," Reproductive
and Cancer Hazard Assessment Section, OEHHA, California Environmental
Protection Agency, May 1997.
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