Revival: Biological Effects of Low Level Exposures to Chemical and Radiation (1992)

BIOSTATISTICAL APPROACHES TO ASSESSMENT 137

Table 7.8. Meta-Analysis Example for Saccharin and Bladder Neoplasia

Dose

FDA Study

Hyperplasia (%)

WARF Study

Tumors (%)

Japanese Study

Tumors (%)

Male Female Male Female Male

0 10/73 (14) 3/85 ( 4) 3/20 (15) 12/20 (60) 19/50 (38)

0.01 6/71 ( 8) 0/81 ( 0) - - -

0.05 - - 2/20 (10) 6/20 (30) -

0.1 4/81 ( 5) 0/81 ( 0) - - -

0.2 - - - - 4/50 ( 5)

0.5 - - 2/20 (10) 9/20 (45) -

1.0 4/76 ( 5) 3/90 ( 3) - - 13/50 (26)

5.0 6/64 ( 9) 5/88 ( 6) 14/20 (70) 18/20 (90) 26/50 (52)

7.5 19/62 (31) 10/76 (13) - - -

Note: FDA and WARF studies: incidence in rats; Japanese study: incidence in mice. Dose is

percent of diet.

analysis can be a powerful tool. Despite publication bias meta-analysis may

be the only way, in many instances, to demonstrate hormetic effects.

The data on saccharin and bladder neoplasia in Table 7.8 will illustrate

the impact that multiple data sources may have. Sources for the data on

saccharin and bladder neoplasia are provided by Downs and Frankowski.15

For each of the five sex-species combinations the response declines at low

doses in comparison to zero dose, plateaus, and then increases as the dose

increases.

QUANTITATIVE DOSE-RESPONSE MODELS

Introduction

Almost without exception the dose-response models studied to date have

focused on harmful effects. Current models thus have limited flexibility.

Some contain mathematical restrictions prohibiting a decrease in response

whenever there is an increase in dose. In such cases the existence of a

threshold or of beneficial effects are excluded automatically from consider­

ation. Some suggestions are proposed for development of more general

models suitable for hormetic dose-response studies.

Model Criteria

The diversity of carcinogenic agents and responses, the variety of expo­

sure settings and routes of administration, and the lack of detailed scientific

knowledge about fundamental cellular processes in cancer all combine to

make it unlikely that a single dose-response model can suffice for all situa­

tions in which a hormetic dose-response model might be required. Still,

some general suggestions about models for U-shaped responses can be put

forth: