INTRODUCTION TO Upercut

Occupational risk assessment has traditionally been based on estimated airborne concentrations of chemical substances in comparison with occupational exposure limits (OELs). The pulmonary route of exposure has been identified as the main route of exposure in industrial hygiene. Only in the last two decades has the issue of occupational health risk posed by dermal exposure been explored. Given the significant decrease in OELs over the past 50 years and the substitution of several volatile agents by substances that are not or that are scarcely volatile, dermal exposure is expected to play an increasingly significant role in occupational hygiene.

While risk assessment strategies for airborne pollutants at the workplace have long been available, cutaneous risk assessment still seems to suffer from a lack of practical tools. In particular, the complexity of the various chemical, physical and physiological processes leading to a chemical reaching a target organ through the skin has prevented the elaboration of exposure limits that would be equivalent to the inhalation occupational exposure limits (OEL).

Just as OEL such as the Threshold limit values (TLV) from the American Conference of Governmental Industrial Hygienists (ACGIH) are the bread and butter of day-to-day occupational risk assessment for airborne exposure, Skin notations are currently the main tool available to hygienists and occupational physicians in order to identify potential risks attributable to systemic toxicity following dermal exposure. The criteria used for assigning a notation generally include one or more of the following depending on availability: experimental data on dermal absorption in human or animals, studies reporting toxic effects following skin exposure, in vitro estimates of dermal penetration, acute dermal toxicity data in animals and quantitative structure-activity relationship (QSAR) models, suggesting an elevated skin absorption potential. However, a methodological framework in order to assess health risk associated with dermal exposure still seems to be lacking. The transparency and rigorousness of the skin notation assignment process have thus been recently questioned, and recent studies have shown significant differences when several list of OELs containing skin notations were compared.

We developed the Upercut tool (‘Utilitaire sur le risque PERCUTané des substances chimiques’) to provide occupational health practitioners with a better portrait of the potential of a substance for cutaneous penetration and systemic toxicity than that given by the yes/no answer from skin notations.

The contributions of the Upercut tool include:

BASIC FUNCTIONS OF THE TOOL

The user selects a chemical substance either from a dropdown list or using a basic search function based on name or CAS number.

Once the chemical is selected, the following information is provided (see help file for more information):

The next step is for the user to choose a dermal exposure scenario for the selected substance. This includes surface of the body exposed (selection of body parts exposed), duration of exposure (in min.) and presence/absence of significant simultaneous inhalation exposure.

After selection of a scenario, Upercut estimates a Dermal Hazard Index (DHR). This quantity represents the ratio of the cutaneous dose to the dose that would be reached if the worker was exposed 8 hours at a respiratory OEL. This estimation is accompanied by an uncertainty analysis based on Monte Carlo simulation, which allows for example to know the probability that the true DHR value would exceed 1 (i.e. cutaneous dose greater than the dose deemed acceptable based on inhalation). See below for a description of how DHR is calculated.

Based on the information summarized by Upercut and the estimated DHR value and its uncertainty, the user can decide of a course of action, which may include taking no further action regarding potential skin exposure, performing a comprehensive dermal exposure assessment study, conducting a biomonitoring survey, or implementing dermal protection measures.

SOURCES OF INFORMATION

Selection of chemicals included in the tool: 2007 list of High production volume (HPV) chemicals from the Organization for economic co-operation and development, and 2010 extraction of the HPV chemicals from the Environmental protection agency (EPA) database. Known corrosive substances were excluded from the final list.

Physico-chemical properties: PHYSPROP database from the Syracuse Research Corporation.
http://www.srcinc.com/what-we-do/product.aspx?id=133

Animal toxicity data and international OELs: Registry of Toxic Effects of Chemical Substances (RTECS) database initially created by the National Institute for Occupational Safety and Health (NIOSH).
http://www.cdc.gov/niosh/rtecs/default.html

Skin notations and OELs: 2010 and 2009 lists of, respectively the ACGIH’s Threshold Limit Values (TLVs®) and Biological Exposure Indices (BEIs®) and List of MAK and BAT Values 2010: Maximum Concentrations and Biological Tolerance Values at the Workplace, Report 46 from the Deutsche Forschungsgemeinschaft.

Skin penetration:
QSAR equations were selected from: Vecchia and A. L. Bunge. Skin absorption databases and predictives equations. In: Transdermal drug delivery, edited by R. H. Guy and J. Hadgraft, New York,NY:Marcel Dekker, 2003, p. 57-141. equation T1, table 1, p88-89.
Intrinsic potential for dermal penetration was evaluated using Magnusson et al.’s proposition: Magnusson BM, Pugh WJ, Roberts MS. Simple rules defining the potential of compounds for transdermal delivery or toxicity. Pharmaceutical Research. 2004; 21(6):1047-1054.

DERIVATION OF A DERMAL HAZARD INDEX (DHR)

This section provides a brief overview of the calculations used to derive the DHR. The complete and detailed approach used can be found in the scientific report (PDF file).

The DHR was calculated using the following general equation:

DHR =  cutaneous.dose
reference.dose

cutaneous.dose refers to a dose in mg of substance expected to cross the skin and enter the blood system. It depends on the duration of exposure, surface of skin exposed, and an estimation of transdermal flux. The first two quantities are selected by the user. The third is estimated from a QSAR equation (see above). This estimation assumes exposure of the chosen surface to an infinite quantity of the substance in a saturated aqueous solution, and that steady state has been reached. The parameters used to estimate the transdermal flux include molecular weight, octanol-water partition coefficient, and water solubility. For gaseous substances, the Henry constant is used to estimate the concentration of an aqueous solution in contact with skin in equilibrium with the vapor concentration set at the OEL.

reference.dose refers to an internal dose of the substance deemed safe for the worker. We derived it by assuming 8 hour inhalation exposure at the OEL with a respiratory absorption fraction of 75%.

When the DHR is above 1, it means that the dose potentially received through the skin would be equivalent or greater to a dose regarded as safe when received through inhalation repeatedly day after day over an entire career.

On the DHR screen, both levels 100% of reference dose (DHR=1) and 10% of reference dose (DHR=0.1) are illustrated. The 10% threshold is shown because it has been mentioned as a criterion for assigning a skin notation to chemicals, and also because we recommend its use when the user indicated that simultaneous inhalation exposure is taking place in addition to skin exposure.

ESTIMATING A REFERENCE DOSE FOR THE DHR CALCULATION

As presented in the previous section, the derivation of DHR requires the availability of a reference dose. Most approaches from which our tool is inspired used OELs to derive a reference dose. Hence, these values represent an exposure concentrations regarded as safe to breathe by reputable organizations and are based on the integration by expert of all available toxicological data. However, OELs are available for only a fraction of existing chemicals. Moreover many different values of OEL may exist for a single substance depending on the organization, and they sometimes are based on local toxic effect such as irritation, not relevant to systemic toxicity.

We developed an OEL database using several sources including the 2010 ACGIH-TLVs, the German 2009 MAK values, and OELs from many countries and organizations reported in the RTECS database. We used this database to maximize the number of chemicals in our tool for which an OEL would be available. We also used it in our calculations to take into account variations in OEL values across organizations for the same chemical.

When no OEL was available for a substance, we used correlation analyses between available OELs and animal toxicity data reported in RTECS to estimate a reference dose.

The Upercut tool issues two different warnings regarding references doses: 1) when the available OEL is known to be based on local toxicity, to the effect that risk is potentially overestimated if systemic effects occur at much higher doses, 2) when the reference dose has been derived using animal toxicity data, to the effect that the DHR estimated is more uncertain.

APPROACH FOR THE UNCERTAINTY ANALYSIS

As can be seen on the DHR screen, the Upercut tool does not only provide one DHR value but rather a distribution of possible values. The text box on the DHR screen provides the probability that the ‘true’ DHR is less than or greater than the chosen threshold (100% or 10%). The uncertainty estimated around each DHR value is substance specific and includes the following parameters:

In average, the uncertainty estimated around a DHR value when an OEL was available corresponds to a ratio of the 90th percentile to the 10th percentile of the uncertainty distribution of 200. It means approximately that for a specific chosen scenario, the greatest plausible value of DHR is 200 times greater than the smallest plausible value. For substances for which an OEL was derived from animal toxicity data, the same ratio is 2 000, corresponding to a much greater uncertainty.

DISCUSSION

The main strength of Upercut is that it addresses present hygienists need to find immediate support in the process of decision-making. It is based primarily on the transfer of information from various sources: as such Upercut can’t be more 'valid' or 'accurate' than these sources would be individually, but it presents an overall picture of all existing information. Hence, indices such as the risk phrases based on animal toxicity are limited by toxico-dynamics and toxico-kinetic extrapolation to humans and to differences between chronic and acute effects. QSAR models used to estimate the DHR are based on an equation derived from a few hundred substances. In addition to this, the ‘acceptable’ doses are based on actual or estimated occupational exposure limits that were developed for exposure by the inhalation pathway. This includes OELs that may be relevant mainly to respiratory irritation, and the dose associated with such OELs may not pose a similar health risk when received by the dermal route. The exposure scenario used to derive DHR requires exposure to an infinite quantity of a saturated aqueous solution of the contaminant, which is probably rarely effective. Furthermore, Upercut does not take into account all of the processes that can affect dermal absorption, such as losses to evaporation or hand-washing, differences in absorption between different areas of the body, metabolisation within the skin, dermal integrity, penetration enhancers, and occlusion. In addition, the tool is designed to assess the risk of systemic health effects following dermal absorption. It does not allow assessment of dermal sensitization. When substances that are dermal sensitizers are selected, a warning message is displayed. A similar warning message is displayed for possible carcinogens and mutagens to advise users that safe levels of exposure may not exist and that minimizing exposure should be a priority. Finally, variations in percutaneous penetration according to the location on the body exposed or on the skin condition (eg. irritated, moisturized, dry ...) were not taken into account. Therefore a series of information that are individually of limited value are presented to identify a potential risk associated with skin chemical exposure. The quantitative uncertainty analysis provided by Upercut around the DHR value allows for a transparent decision making process. This project endeavored to transfer existing knowledge in the field of chemical dermal risk analysis to the practical field of occupational hygiene. We insist that Upercut is not a risk assessment but a hazard assessment tool: it is not designed to provide a proper evaluation of risk but to indicate the need to perform such an evaluation.

CONTACT INFORMATION

Jérome Lavoué (Jerome.lavoue@umontreal.ca)
- Chercheur / Research scientist.  Centre de recherche du CHUM
- Professeur agrégé / Associate professor.  Université de Montréal