Estimation of False Negative Rates for the In Vivo
Rabbit Dermal Irritation Assay
N.Y. Choksi1,2, R.R. Tice1,2, J.H. Haseman3, W.S. Stokes2
1. ILS Inc., RTP, NC
2. NICEATM, RTP, NC
3. NIEHS, RTP, NC
Alternative in vitro test methods proposed to substitute or replace an
in vivo test method should provide equivalent or improved protection of human or animal health
in order to gain regulatory and general acceptance. The ICCVAM and NICEATM are collaborating with the
ECVAM to conduct a validation study of three in vitro dermal irritation assays. To assess the
acceptability of these in vitro assays, an effort was undertaken to estimate the false negative
rate of the in vivo test as defined by its ability to consistently identify irritants,
mild irritants, and non-irritants according to the Globally Harmonized Classification Scheme.
Data for 187 substances was obtained from the ECETOC database for skin irritation and corrosion.
The distribution of rabbits with mean erythema or oedema scores of <1.5, between 1.5 and 2.3, or
>2.3 was determined for each of the substances classified as "negative", "mild irritant" or
"irritant". Since the true classification of each substance is unknown, a simplifying assumption
was made that the results are correct for substances tested once only. For multiple-tested
substances, the classification obtained from a majority of the studies was used. The analysis
indicated: (1) the likelihood of a mild irritant being under-classified as a non-irritant was
<5% when based on all substances and <10% when based on multiple-tested substances, (2) the
under-classification rate of irritants as non-irritants was <1%, and (3) the under-classification
rate of irritants as mild irritants ranged from 9-30%, depending on whether all substances or only
multiple-tested substances were considered. Additional in vivo irritation data for studies
using currently accepted procedures was requested from US federal agencies and industry. Appropriate
data received will be added to the database and the false negative analysis refined. This evaluation
emphasizes the need for high quality in vivo dermal irritation data that can be used to
assess the performance of proposed new alternative test methods. ILS staff supported by NIEHS
contract N01-ES-35504.
This page was last updated May 9, 2007
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