The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
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T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s<br />
10.41 <str<strong>on</strong>g>The</str<strong>on</strong>g> sec<strong>on</strong>d meta-analysis draws <strong>on</strong> the work <str<strong>on</strong>g>of</str<strong>on</strong>g> Olsen et al., 23 am<strong>on</strong>g others, and c<strong>on</strong>cluded<br />
that, although the relevant available data are ‘fragmentary’, 24 the c<strong>on</strong>cordance between<br />
short-term toxic effects <str<strong>on</strong>g>of</str<strong>on</strong>g> new pharmaceuticals in <str<strong>on</strong>g>animals</str<strong>on</strong>g> and humans (during clinical<br />
trials) was 71 percent. This means that 71 percent <str<strong>on</strong>g>of</str<strong>on</strong>g> human acute toxicities resulting from<br />
compounds that entered clinical trials were predicted by pre-clinical safety pharmacology or<br />
toxicity studies in <str<strong>on</strong>g>animals</str<strong>on</strong>g>. It is noteworthy that this c<strong>on</strong>clusi<strong>on</strong> has been used as part <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
cases both ‘for’ and ‘against’ the predictive value <str<strong>on</strong>g>of</str<strong>on</strong>g> pre-clinical animal studies: thus while<br />
70 percent <str<strong>on</strong>g>of</str<strong>on</strong>g> human toxicities were predicted, 30 percent were not, and the rodent tests<br />
al<strong>on</strong>e predicted <strong>on</strong>ly 43 percent <str<strong>on</strong>g>of</str<strong>on</strong>g> human toxicities. 25<br />
10.42 It is also worth noting that the toxic events c<strong>on</strong>sidered by Olsen et al. are likely to be at the<br />
more minor end <str<strong>on</strong>g>of</str<strong>on</strong>g> the spectrum <str<strong>on</strong>g>of</str<strong>on</strong>g> potential adverse effects. Compounds causing significant<br />
damage to <str<strong>on</strong>g>animals</str<strong>on</strong>g> would not have entered clinical trials. Reliable systematic data <strong>on</strong><br />
compounds eliminated before human dosing because <str<strong>on</strong>g>of</str<strong>on</strong>g> major organ toxicity in <str<strong>on</strong>g>animals</str<strong>on</strong>g> are<br />
not available. It is therefore not possible to judge how many compounds were rejected<br />
because <str<strong>on</strong>g>of</str<strong>on</strong>g> their adverse effects in <str<strong>on</strong>g>animals</str<strong>on</strong>g>. 26 As before, this observati<strong>on</strong> could be used to<br />
support or c<strong>on</strong>test the scientific validity <str<strong>on</strong>g>of</str<strong>on</strong>g> animal tests. On the <strong>on</strong>e hand, it can be argued<br />
that actual c<strong>on</strong>cordance is greater than 70 percent, when the animal tests showing adverse<br />
effects too significant to proceed to human trials are taken into account. On the other, it<br />
might be argued that animal <str<strong>on</strong>g>research</str<strong>on</strong>g> may lead to the loss <str<strong>on</strong>g>of</str<strong>on</strong>g> potentially useful medicines for<br />
humans as compounds might be removed in the screening process because <str<strong>on</strong>g>of</str<strong>on</strong>g> significant<br />
toxicity in <str<strong>on</strong>g>animals</str<strong>on</strong>g> which would perhaps not occur in humans. However, those defending the<br />
use <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g> would argue that the opti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> ‘losing’ some compounds in this way can be<br />
viewed as preferable to exposing humans to medicines that have not underg<strong>on</strong>e prior testing.<br />
CHAPTER 10 SUMMARY OF SECTION 2<br />
10.43 Finally, it should be noted that the Ols<strong>on</strong> study <strong>on</strong>ly c<strong>on</strong>sidered toxic events observed in<br />
human clinical trials, i.e. short-term effects. L<strong>on</strong>ger-term toxicities such as carcinogenicity<br />
and teratogenicity were not assessed. For these l<strong>on</strong>g-term toxicities it has been difficult to<br />
establish the validity <str<strong>on</strong>g>of</str<strong>on</strong>g> animal tests 27 which have been criticised by toxicologists. 28 Thus the<br />
c<strong>on</strong>cordance between animal and human l<strong>on</strong>g-term toxicities, if it could have been<br />
measured, may prove lower than found by Ols<strong>on</strong> et al. for short-term toxicities. At the same<br />
time it needs to be acknowledged that assessment <str<strong>on</strong>g>of</str<strong>on</strong>g> l<strong>on</strong>g-term toxicity is a highly complex<br />
process. For example, while it may be straightforward to identify a number <str<strong>on</strong>g>of</str<strong>on</strong>g> people who<br />
have taken a certain medicine at some point in the past, it may be less straightforward to<br />
correlate possible negative states <str<strong>on</strong>g>of</str<strong>on</strong>g> health which occur, for example, a decade after the<br />
medicine has been used. Since people may have taken a range <str<strong>on</strong>g>of</str<strong>on</strong>g> other medicines in the<br />
meantime, and since factors such as lifestyle or exposure to chemicals in the workplace may<br />
also play a role, many factors need to be c<strong>on</strong>sidered.<br />
23 Ols<strong>on</strong> H Bett<strong>on</strong> G, Robins<strong>on</strong> D et al. (2000) C<strong>on</strong>cordance <str<strong>on</strong>g>of</str<strong>on</strong>g> the toxicity <str<strong>on</strong>g>of</str<strong>on</strong>g> pharmaceuticals in humans and in <str<strong>on</strong>g>animals</str<strong>on</strong>g><br />
Regulat Toxicol Pharmacol 32: 56–67.<br />
24 <str<strong>on</strong>g>The</str<strong>on</strong>g> authors note that much <str<strong>on</strong>g>of</str<strong>on</strong>g> the relevant informati<strong>on</strong> is held by government regulatory authorities and pharmaceutical<br />
companies and is not publicly available in the peer-reviewed scientific literature. <str<strong>on</strong>g>The</str<strong>on</strong>g> authors state that they can ‘<strong>on</strong>ly learn<br />
from experience and then <strong>on</strong>ly if we have access to informati<strong>on</strong>’.<br />
25 Animal Procedures Committee (2003) Review <str<strong>on</strong>g>of</str<strong>on</strong>g> the cost-benefit assessment in the use <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g> in <str<strong>on</strong>g>research</str<strong>on</strong>g> (L<strong>on</strong>d<strong>on</strong>: HO).<br />
26 Greaves P, Williams A and Eve M (2004) First dose <str<strong>on</strong>g>of</str<strong>on</strong>g> potential new medicines to humans: how <str<strong>on</strong>g>animals</str<strong>on</strong>g> can help. Nat Rev<br />
Drug Disc 3: 226–36.<br />
27 Lo WY and Friedman JM (2002). Teratogenicity <str<strong>on</strong>g>of</str<strong>on</strong>g> recently introduced medicati<strong>on</strong>s in human pregnancy. Obstet Gynecol 100:<br />
465-73.<br />
28 For example, Ennever FK and Lave LB (2003). Implicati<strong>on</strong>s <str<strong>on</strong>g>of</str<strong>on</strong>g> the lack <str<strong>on</strong>g>of</str<strong>on</strong>g> accuracy <str<strong>on</strong>g>of</str<strong>on</strong>g> the lifetime rodent bioassay for<br />
predicting human carcinogenicity. Reg Toxicol Pharmacol 38:52-57; Johns<strong>on</strong> FM (2003) How many high producti<strong>on</strong> chemicals<br />
are rodent carcinogens? Why should we care? What do we need to do about it? Mutat Res 543:201-15; and Gottman E,<br />
Kramer S, Pfahringer B et al. (2001) Data quality in predictive toxicology: reproducibility <str<strong>on</strong>g>of</str<strong>on</strong>g> rodent carcinogenicity<br />
experiments Envir<strong>on</strong> Health Perspect 109:509-14; Kennedy DL, Uhl K and Kweder SL (2004) Pregnancy exposure registries<br />
Drug Saf 27:215-28.<br />
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