UPDATE TO Comments on Species Sensitivity Differences Jay B. - - PowerPoint PPT Presentation

Jay B. Silkworth, Ph.D. General Electric Company Global Research Center Niskayuna, NY 12309 October 27, 2010 Washington, DC

UPDATE TO

Comments on Species Sensitivity Differences

• The Draft Reanalysis uses human data to derive new RfD

and CSFs for TCDD only.

• To apply these values to real world mixtures of DLCs, EPA

proposes to apply the current WHO TEFs which are derived from rodent studies.

• But, NAS 2006 recommends ‘adjusting for species sensitivity

differences’ if evidence available.

• Some human in vitro derived factors are available, e.g., PCB

126 (0.1 in rodents and rodent cells) is 0.002 in human cells. This is a growing and robust data set.

Application of inconsistently derived risk values

3

• 14 -13 -12 -11 -10 -9
• 8
• 7
• 6
• 5
• 4

50 100 150 200 250 300 Rhesus (3) Rat (5) HepG2 (5) Donors (3)

TCDD

• 14 -13 -12 -11 -10 -9
• 8
• 7
• 6
• 5
• 4

50 100 150 200 250 300 Rhesus (3) HepG2 (3) Donors (3) Rat (3)

PCB 126

• 14 -13 -12 -11 -10 -9
• 8
• 7
• 6
• 5
• 4

50 100 150 200 250 300 Rhesus (3) Rat (3) HepG2 (3) Donors (3)

Aroclor 1254

Concentration (Log M)

Human cells

EROD Human cells are ~10x less sensitive to TCDD than rhesus and rat cells to but they are also 100x less sensitive to PCB 126 and Aroclor

Human cells Human cells

Response

*Adapted from Silkworth et al. (2005). Toxicol Sci. 87(2), 508-519

100 x 10 x

Hepatocytes

REPPCB126 Density (Arbitrary Units) 1 2 3 4 0.0001 0.001 0.01 0.1 1 Human Rat

n= 79 genes n= 47 genes

Monte Carlo analysis of distribution around geomean REPPCB126

5

Human insensitivity to PCB126 is true for most responding genes

Toxicogenomic REP modeling

1Sutter et al. Tox. Sci. in press, 2010

Show same species sensitivity differences

Rat Human

REP based on EC50s is 0.0027 not 0.1 Keratinocytes TCDD PCB126

1Sutter et al. Tox. Sci. in press, 2010

REP based on threshold dose is 0.0022 not 0.1

Human

Keratinocytes TCDD PCB126

TEF REP WHO TEF (Rodent based ) 0.1 Human Liver 0.002 Keratinocytes1 EC50 0.0027 Threshold 0.0022 Lymphocytes2 0.003

Why continue to use rodent-derived TEFs when human-derived REPS are available?

1Sutter et al. Tox. Sci. in press, 2010 2van Duursen, et al., Organo Halogens, 2010

• Many human genes are far less sensitive than rat genes to

these chemicals.

• Chemical potencies of DLCs vary across species.
• Human variability is likely less than inter-species variability.
• Humans genes clearly respond with nonlinear threshold-

dependent dose-response curves.

• Animals are not accurately predicting human responsiveness.

Summary

Thank you