1) Allow only those routes with both dose and route-specific RAV data to contribute to a chemical's TEP, effectively treating chemical doses via routes without RAVs as completely safe (contributing zero risk to the TEP), or 2) Allow cross-route extrapolation, utilizing available route-specific RAVs as a default RAV for exposure routes with data gaps.

It is inappropriate to treat the often substantial chemical doses accumulated through pathways without route-specific RAVs as without health risk. As a general rule, any available risk assessment value is assumed to apply to other routes of exposure lacking toxicity data, unless there is a clear toxicological rationale against making this assumption. While there are problems involved in presuming a chemical is equally toxic across different exposure routes, the increased uncertainty created by this default assumption is much less of a problem than the bias in rankings that would be produced by a system that presumes that dose routes with RAV data gaps are always without risk.

The following chemical-specific decisions were made about the cross-route applicability of specific risk assessment values (RAVs, based on the following decision rules:

APPLICATION OF INGESTION RAVS TO OTHER ROUTES OF EXPOSURE
It is assumed that it is appropriate to utilize ingestion risk assessment values to fill data gaps for other routes of exposure because this is conventional regulatory agency practice. This assumption is widely accepted in the derivation of cancer potency factors: 52 of the 90 carcinogenic substances with cancer TEPs in Scorecard have been assigned identical values for both ingestion and inhalation potency values by authoritative regulatory sources. Most of the remaining potency differences are within a factor of five and attributable to the derivation methods of different agencies rather than to route-specific toxicity differences. Only 1,1-dimethylhydrazine, arsenic, lead, 1,2-dibromoethane, and propylene oxide exhibit significant differences in potency by route of exposure.

There is less similarity between ingestion and inhalation noncancer risk assessment values. 47 of 114 substances with noncancer TEPs have inhalation and ingestion reference doses that are within a factor of five and attributable to the derivation methods of different agencies. 22 substances are significantly more toxic via ingestion (with four: vinyl chloride, trichloroethylene, acetone, and hexachloro-1,3-butadiene being more toxic by a factor of 50 or more). 45 substances are significantly more toxic via inhalation (with 23 being more toxic by a factor of 50 or more). Most of the largest route-specific toxicity differentials are observed with metals (chromium, beryllium, manganese, copper, nickel, zinc, barium, selenium, and cadmium). In general, route-specific toxicity differences for these metals are attributable to higher absorption coefficients for inhalation exposures (except for copper and nickel) and differential toxicity based on portal of entry effects (Owen, 1990).

Based on this distributional comparison of ingestion and inhalation risk assessment values, it is clear that compounds with ingestion RAVs are likely to have inhalation RAVs of comparable or higher toxicity. The decision to utilize ingestion RAVs as default RAVs is therefore less likely to result in biased chemical rankings than the alternative presumption that inhalation doses are without any health risk.

APPLICABILITY OF INHALATION NONCANCER RAVS TO INGESTION AND DERMAL ROUTES
OF EXPOSURE Case-by-case review is required to evaluate the applicability of inhalation RAVs to other routes of exposure because there is no widely accepted regulatory approach to this type of data gap (relatively few compounds have inhalation RAVs and not ingestion RAVs). In general, if the critical effect underlying RAV derivation involved any other organ system than respiratory, it was presumed this endpoint could also be caused by ingestion or dermal exposure. It was not possible to ascertain the extent to which an inhalation RAV (converted to a mg/kg-d) dose would over- or under-estimate potency by other routes. Based on available data from acute studies for the compounds at issue, inhalation is clearly not always the most toxic route of exposure.

The following decision rules were used to identify inhalation noncancer RAVs that would be inappropriate to apply to ingestion or dermal exposures: 1) if agency deriving RAV explicitly limited it to inhalation exposures 2) if critical effect of RAV was based on no observed toxicity, or on respiratory system impacts only and no other studies (including acute) reported non-respiratory effects by other exposure routes 3) special case judgments, when the toxic potency associated with respiratory effects clearly overstated a compound's potential potency for other adverse effects (e.g., cobalt).

APPLICABILITY OF INHALATION CANCER RAVS TO INGESTION AND DERMAL ROUTES OF
EXPOSURE The following decision rules were used to identify inhalation cancer RAVs that would be inappropriate to apply to ingestion or dermal exposures: 1) if agency deriving RAV explicitly limited it to inhalation exposures 2) if cancer target organs only involved respiratory system

REFERENCE
Owen, B.A. Literature-derived absorption coefficients for 39 chemicals via oral and inhalation routes of exposure. Regulatory Toxicology and Pharmacology 11: 237-252. 1990.