Meeting report: moving upstream-evaluating adverse upstream end points for improved risk assessment and decision-making.
BACKGROUND
Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment.


OBJECTIVE
Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available.


CONCLUSIONS
Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects.


CONCLUSIONS
For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.
Woodruff
Tracey J
TJ
Department of Obstetrics and Gynecology, University of California, San Francisco, California, USA. woodrufft@obgyno.uscf.edu
Zeise
Lauren
L
Axelrad
Daniel A
DA
Guyton
Kathryn Z
KZ
Janssen
Sarah
S
Miller
Mark
M
Miller
Gregory G
GG
Schwartz
Jackie M
JM
Alexeeff
George
G
Anderson
Henry
H
Birnbaum
Linda
L
Bois
Frederic
F
Cogliano
Vincent James
VJ
Crofton
Kevin
K
Euling
Susan Y
SY
Foster
Paul M D
PM
Germolec
Dori R
DR
Gray
Earl
E
Hattis
Dale B
DB
Kyle
Amy D
AD
Luebke
Robert W
RW
Luster
Michael I
MI
Portier
Chris
C
Rice
Deborah C
DC
Solomon
Gina
G
Vandenberg
John
J
Zoeller
R Thomas
RT
D003657:Decision Making; D006801:Humans; D018570:Risk Assessment