Estimating variabilities of toxicological endpoints of concerns to the Agency for Toxic Substances and Disease Registry (ATSDR) 公开

Abstract

Background: A significant number of chemicals in governmental databases lack health guidance values (HGVs) that are essential to protect public during chemical emergencies. In public health risk assessments, computational models could be used to fill these gaps when better toxicological information are not available. HGVs are commonly derived from toxicological endpoints such as benchmark dose (BMD) or a no-observed-adverse-effect level (NOAEL) and in absence of them, a lowest-observed-adverse-effect level (LOAEL) or median lethal dosage (LD50). Because these endpoints are measured quantities, they are expected to carry a certain level of natural variability. However, the magnitude of such variability in each endpoint is currently unknown.

Objective: In the present study, we assessed variabilities of LOAELs, NOAELs, and LD50s using data from ATSDR toxicological profiles of chemicals and other publicly available databases.  

Methods: We estimated variability of each toxicological endpoint using distribution of sample variances of endpoints per chemical in acute, intermediate, and chronic exposure durations. The variability estimates were then used to obtain scaling factors to derive lower bounds on respective endpoints. Additionally, we assessed the influence of experimental test species, target organ systems, and availability of Minimum Risk Levels (MRLs) on variability.

Results: Variability of LD50s was approximately half that of LOAELs whereas difference in variability of LOAELs and NOAELs was smaller. Matching endpoints by test species had no significant impact (except in intermediate duration endpoints) whereas matching target systems lowered NOAELs variability across all three exposure durations. Additionally, the availability of MRLs did not significantly affect variabilities of corresponding endpoints.

Conclusions: The findings from this study provide insight into variabilities of toxicological endpoints in ATSDR and other governmental databases, which could be useful in public health guidance and risk assessments.  

Table of Contents

Table of Contents

Introduction .......................................................................................................... 1

Methods .................................................................................................................. 4

Data Compilation.................................................................................................... 4

Data analysis ............................................................................................................ 8

Results .................................................................................................................. 12

Data description .................................................................................................... 12

LD50s: ...................................................................................................................... 12

L(N)OAELs: .......................................................................................................... 13

Data analysis .......................................................................................................... 14

Accessing homogeneity of variances assumption ................................ 14

Variance estimation of LD50s ........................................................................ 15

Variance estimation of L(N)OAELs ............................................................ 18

Variability versus sample size ...................................................................... 23

Derivation of factors based on SDs ............................................................ 24

Discussion ........................................................................................................... 25

Variability of LD50s and comparison to previous studies .................. 25

Variability of L(N)OAELs and comparison to LD50s ............................. 26

Scaling factors to derive a lower bound on an endpoint ..................... 28

Further study .......................................................................................................... 29

Conclusions ............................................................................................................. 31

References ........................................................................................................... 32

Appendix A: Tables .............................................................................................. i

Appendix B: Figures ......................................................................................... xiv

About this Master's Thesis

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School	Rollins School of Public Health
Department	Biostatistics
Subfield / Discipline	Biostatistics - MPH & MSPH
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Environmental Health
关键词	LD50 variability

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