# Presentation: 527430

## Aldicarb Human Volunteer StudyInveresk Clinical Research1991-1992

- The EPA Human Studies Review Board Meeting
- Rosslyn, VA
- 4-6 April, 2006
- Dr. Neil Carmichael
- Global Head of Toxicology
- Bayer CropScience

## Objectives of Aldicarb Human Study

- Characterize the dose response and time course of ChE inhibition following administration of aldicarb using a double blind design
- Demonstrate the relative sensitivity of male and female humans compared to animals
- Address questions raised by regulatory authorities about aldicarb toxicity and risks to humans.

## Aldicarb Ethics Review

**Value of research to society**
*Aldicarb is a carbamate insecticide, nematicide, and acaricide used for 35 years to improve crop production*
*The human data have been published in scientific literature (Handbook of Pesticide Toxicology, 2001) and presented in several posters at SOT national meetings*
**Independent ethical review**
*IRB members independent of ICR,  IRB review conducted, lay summaries modified as requested*
- Original protocol and lay summary submitted to the Ethics Committee (19 Dec, 1991)
- Documents revised subsequent to committee meeting to incorporate recommendations (24 Dec, 1991)
- A modified Lay Summary and a letter to the volunteer’s GP for the inclusion of female subjects was approved by the Ethics Committee (memo dated 19 Feb, 1992)

## Aldicarb Ethics Review

**Informed consent**
*Lay summary provided to candidates; consent forms signed*
*Aldicarb mentioned as a ‘drug’ in a few instances but clearly described as an insecticide/nematicide*
*Dose range given for males in lay summary; doses specified for females *
**Respect for potential and enrolled subjects**
*Candidates free to withdraw at any time*
*Privacy of subjects not compromised*
**Conclusion:  The study was conducted ethically**

## Study Design

- Double blind, placebo controlled
- Aldicarb was given as a single oral dose to healthy male and female subjects.
- Dose selection based on previous human studies and animal data.
- Doses administered were: placebo, 0.01, 0.025, 0.05, and 0.075 mg/kg.
- Full range of appropriate clinical measurements were made at intervals before and after dosing
- Samples were taken for urinalysis, clinical chemistry including RBC and plasma ChE, and hematology before and** **after dosing.

## Study Results

- Dose-related ChE inhibition was observed.
- Recovery from ChE inhibition was rapid even at the highest dose.
- No treatment related clinical signs were observed in males or  females at 0.05 mg/kg or below.
- A treatment related clinical effect was observed in one male in the highest dose group, based on generalized sweating.
- Sweaty palms observed sporadically in all dose groups and was not clearly related to treatment.
- Based on placebo control, less than 20% inhibition of RBC ChE at 0.025 mg/kg in both sexes and no inhibition in RBC ChE in males at 0.01 mg/kg

## Regulatory Use of Human Study

- In 1993, EPA accepted study for use in the risk assessment process
- EPA established a RfD of 0.001 mg/kg/day based on a combination of human and dog data  and a 10X safety factor for intraspecies variability
- WHO  and EU established a RfD of 0.003 mg/kg/day based on the human study and a 10X safety factor for  intraspecies variability
- Study has been validated by two EPA SAB/SAP meetings (1992 and 1999).

## BCS Position on Use of Human Study in Risk Assessment

- The human volunteer study represents the most relevant and appropriate data for setting the Reference Dose and the interspecies safety factor
- Covers doses in the appropriate range (<0.05 mg/kg) for establishing the POD
- Is supported by a large animal database which indicates consistency across species
- Statistical analysis demonstrates that at doses relevant for risk assessment, females are no more sensitive than males

## General Comments

- BCS recognizes the role of the HSRB in providing guidance and oversight to those sponsoring intentional dosing studies for submission to EPA
- HSRB’s is charged with reviewing the ethical and scientific considerations pertaining to study conduct including the scientific justification and risk/benefit questions
- It is inappropriate for EPA to ask the HSRB to render weight-of-evidence (WOE) judgments with only a limited sampling and summarization of the available information and data