# Presentation: 895416

## Application of Life Stage Specific Data in the Risk Assessment for Children:

**Case Study Presentation Using Pesticides**
- Susan Makris1, Kacee Deener3, Vicki Dellarco5, Elizabeth Doyle6, Elaine Cohen-Hubal4, Ginger Moser2, Stephanie Padilla2, Tammy Stoker2
- 1U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment;
- 2US EPA, ORD, National Health and Environmental Effects Research Laboratory;  3US EPA, ORD, National Center for Environmental Research;
- 4US EPA, National Exposure Research Laboratory;  5US EPA, Office of Pesticide Programs;   6US EPA, Office of Water

- How should life-stage specific data (i.e., prenatal, postnatal, and peri-pubertal exposures and toxicological effects) be addressed in the risk assessments for specific pesticides?
- What additional information may be necessary to fully characterize risk to children from specific pesticide exposures?

**Research Goals**

**Impact and Outcomes**

**Results/Conclusions**

**Future Directions**

**Science Question**

- ORD has been instrumental in developing a number of tools (including risk assessment guidelines, testing guidelines, guidance documents, and workshops) that have had a critical positive impact on pesticide risk assessment in the Program Offices.  These efforts have generally been conducted as collaborative inter-office working group projects under the leadership of ORD/NCEA.
- Historically, ORD has also contributed to the risk assessments of specific individual pesticides or classes of pesticides through test methods development, the generation of data, and consultation with the Program Offices. Example cases, where ORD input was essential to the interpretation of life-stage specific susceptibility and was critical to the assessment of risk to children’s health, are chlorpyrifos and atrazine, two widely-used pesticides with documented potential for exposure to children.  Extensive collaboration and consultation between ORD and the Program Offices occurred during the process of developing the risk assessments.

- Research conducted or supported by ORD contributed to the characterization of life-stage specific susceptibility issues for each of these two chemicals.  In the case of chlorpyrifos, age-related sensitivity to cholinesterase inhibition was characterized in NHEERL studies, and the assessment of children’s exposure to chlorpyrifos was developed and/or refined through the activities of NERL and NCER.  For atrazine, seminal research was conducted by NHEERL scientists to identify the critical non-cancer mode of action for risk assessment, i.e., disruption to the hypothalamic-pituitary-gonadal axis during development. Overall, for these two pesticides, ORD studies provided confirmation of susceptibility to the young, support for decisions regarding the adverse consequences of the observed effects, a basis for extrapolation from animal data to potential human response, methodologies to assess exposure to children, and information critical in identifying the point of departure for risk assessments conducted by OPP and OW.

- Development of guidelines and guidance for risk assessment by ORD has advanced the state of the knowledge in specific scientific disciplines as they relate to susceptibility, and have helped provide a strong link between ORD laboratory research efforts and the risk assessment process. This has resulted in higher quality, defensible decision-making by the Program Offices and in greater consistency in risk assessment practices across the Agency.
- For chlorpyrifos and atrazine, risk management decisions made by the Program Offices addressed the protection of susceptible populations.  Residential uses of chlorpyrifos were cancelled in mitigation efforts that became effective in 2001.  Earlier CDC biomonitoring studies suggest that levels of urinary metabolites that are indicative of chlorpyrifos exposure are lower in the 1999-2000 period compared to the 1988-1994 period.  Additionally, in an NCER-supported study of an urban minority cohort of newborn babies and their mothers (Whyatt et al., 2004), levels of chlorpyrifos in personal air and blood samples were substantially decreased from 1998-2002, and correlations between chlorpyrifos exposure levels and decreased birth weight/length observed in 1998 were no longer apparent in 2002. For atrazine, risk communication efforts were critical in refocusing public perception of potential risks, away from long-term cancer concerns (the focus of past risk assessments) and towards non-cancer risks to susceptible populations.

- There are multiple on-going efforts to further develop and/or refine guidance for  children’s health risk assessment.
- Further ORD Research on the basis of susceptibility for specific chemicals or chemical classes will be important in cumulative risk assessments.

- _Atrazine_:
- Cooper, RL et al. (1996) *Reprod. Toxicol.* 10(4):257-264.
- Stoker, TE et al. (1999)** ***Tox. Sci. *52(1):68-79.
- Cooper, RL et al. (2000) *Tox. Sci.* 53:297-307.
- Stoker, TE et al.** **(2000) *Tox. Sci. *58:50-59.
- Laws, SC et al. (2000) *Tox. Sci.*** **58(2):366-76.
- Stoker, TE et al. (2002) *Tox. Sci.*** **67(2):198-206.
- Laws, SC et al. (2003) *Tox. Sci.* 76(1):190-200.
- USEPA (2003) Atrazine IRED
-   (http://www.epa.gov/oppsrrd1/reregistration/atrazine)
- _Chlorpyrifos_:
- Atterberry, TT et al. (1997) *Tox. Appl. Pharm*. 147(2):411-418.
- Boone, JS et al. (2001) *Env. Health Persp*. 109(11):1109-1114.
- Das, KP and Barone, S (1999) *Tox. Appl. Pharm*. 160:217-230.
- Carr, RL et al. (2001) *Tox. Sci*. 59(2):260-267.
- Hunter, DL et al. (1999) *Tox. Appl. Pharm*. 158:16-23.
- Lassiter, TL et al. (1998) *Tox. Appl. Pharm.* 152:56-65.
- Lu, C and RA Fenske (1999) *Env. Health Persp*. 107(6):463-467.
- Moser, VC et al. (1998) *Tox. Sci*. 46:211-222.
- Moser, VC and Padilla, S (1998) *Tox. Appl. Pharm*. 145:158-174.
- Whyatt, RM et al. (2004) *Env. Health. Persp*. 112(10):1125-1132.
- USEPA (2002) Chlorpyrifos IRED
-   (http://www.epa.gov/oppsrrd1/REDs/chlorpyrifos_ired.pdf)

**References**

**Guidance Development**

**NCEA**

**NHEERL**

**NERL**

**OPPTS**

**OW**

**OAR**

**NCER**

- Examples of Life-stage Specific Guidance

** **_**Risk Assessment Guidelines**_** **
- Developmental Tox, revised, 1994
- Reproduction, 1996
- Neurotoxicity, 1998
- Carcinogenicity (draft), 1999

** **_**Guidance Documents**_** **
- FQPA/10X Task Force, 1999
- Review of the RfD and RfC Processes, 2002
- Child-Specific Exposure Factor Handbook, 2002
- Children’s Health Risk Assess. Framework, in progress

** **_**OPPTS Test Guidelines**_** **
- Developmental Tox, revised, 1998
- Reproduction/Fertility, revised, 1998
- Developmental Neurotox, revised, 1998
- Developmental Immunotox, in progress

** **_**Life-Stage Specific Methods Development**_** **
- Biomarker assays
- Endocrine assays

**ATRAZINE**

**CHLORPYRIFOS**

- Registrant-Generated Toxicology and Exposure Data

- NHEERL Studies

- Registrant-Generated Toxicology and Exposure Data

- NHEERL Studies

- Public perception of potential risk was refocused away from cancer and onto neuroendocrine-mediateds reproductive/developmental risks from atrazine exposure to susceptible populations

- A number of residential uses of chlorpyrifos were cancelled or limited; public awareness of potential risks to susceptible populations was raised; preliminary data suggest positive outcomes on these populations (Whyatt et al. 2004)

- Critical non-cancer MoA for risk assessment identified: disruption to the hypothalamic-pituitary-gonadal axis during development

- Age-related sensitivity was characterized for the established MoA (cholinesterase inhibition - ChEI);

- ChEI Data

- Puberty Studies

- Atrazine – Interim Reregistration Eligibility Decision (2003)

- Chlorpyrifos – Reregistration Eligibility Decision (2000)

- NCER STAR Grant Studies

- Juvenile sensitivity: Carr et al. 2001, Atterberry et al. 1997

- Exposures to farm children; Lu and Fensky 1999

- Gestation exposures: Hunter, et al.; Lassiter, et al. 1998

- Juvenile sensitivity: Moser and Padilla; Moser et al., 1998

- MoA for develop. tox: Das & Barone, 1999, Song et al. 1997

- Disrupted hypothalamic control of pituitary-ovarian function, Cooper et al. 2000

- Delayed male puberty: Stoker et al., 2000, 2002

- Delayed female puberty: Laws et al., 2000, 2003

- Suppressed Estrogen-induced surges of LH and prolactin, Cooper et al., 1996

- Suppressed prolactin; developmental prostatitis: Stoker et al., 1999

- Residential (child) exposures: Boone et al. 2001

- Based upon information on sensitivity and susceptibility of the young, and on residual uncertainties regarding potential adverse effects following exposure of children to chlorpyrifos, the 10X FQPA Safety Factor was applied to all children’s health risk assessments for chlorpyrifos.