The BEEL Committee consists of members of the Biological Monitoring and Workplace Environmental Exposure Level (WEEL) Committees of the American Industrial Hygiene Association.

The Committee was formed in 2000. Its composition was: Shane Que Hee (Chairperson, UCLA); Mark Boeniger, NIOSH; Carol Boraiko, Atofina Chemicals; Janice Fiori, Lilly Research Laboratories; Tony Havics, pH2 Environmental; Tom Klingner, Colormetric Laboratories; Leena Nylander-French, Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill; and Jeffrey Paull, TechLaw.

The Mission Statement of the BEEL Committee:
“To provide the professional industrial hygienist with recommendations for providing the highest level of workplace safety and health relative to chemicals whose dominant mode of absorption is NOT by inhalation but through the skin or ingestion, and for which biological monitoring markers are required to detect exposure and to assess the extent of exposure. Such chemicals typically have low vapor pressures, and greater than 30% contribution to the internal exposure by the non-inhalation route.” Traditional industrial and environmental hygiene has focussed on inhalation exposure hazards. Chemicals known to absorb through the skin have traditionally been accorded the notation “skin” by OSHA, NIOSH and ACGIH. The recommended air guideline (PEL, REL, or TLV) protects only for inhalation exposure and the industrial and environmental hygienist must use “professional judgment” to assess the risk of non-inhalation routes. None of these bodies has attempted to produce guidances for hygienists for chemicals whose dominant mode of absorption is through the skin or ingestion. Some examples of chemical classes whose major worker health hazard is through skin absorption include: aromatic amines of high molecular weight; PCBs; PAHs; non-volatile pesticides; and organometallic compounds.

The members of the BEEL Committee agreed that the method of decision-making would be by expert consensus of the best industrial hygiene practice for the item on hand so as to produce a higher standard of professional industrial hygiene practice.

To make the task of producing Documentations and BEELs more manageable for each material considered, it was agreed to consider:

• Only the most sensitive toxic effects
• Published and unpublished data
• Theoretical models
• Statistically defensible data and models
• Published risk assessments
• Published hygienic guidelines and their risk assessments
• Regulations and their basis
• Risk assessments for the route of entry (skin or oral ingestion) as first preference
• Availability of biological monitoring data (for example, correlation of urine marker concentrations with skin exposure data; marker half-time data; fraction of absorbed dose that is excreted; marker concentrations in exposed workers in the United States and other countries), skin sampling methods, and analytical methods.
• The biological equivalent approach

Later on it was also agreed to:

• Present the essentials of each Documentation at Forums and Roundtables at the AIHCE to allow public comment
• Publish the BEEL itself in the WEEL booklet and in the appropriate short format in the WEEL Documentation booklet
• Publish each full BEEL Documentation in a peer-reviewed journal

The first chemical chosen was MDA because:

• It was a single chemical and would allow the framework of the BEEL process to be established in the minimum time. Its physical constants were known and invariant unlike for mixtures.
• It had published risk assessments by the Dutch Expert Committee on Occupational Standards (DECOS) and ATSDR.
• The major route of exposure was skin according to OSHA and the scientific literature
• Complementary animal and human data existed
• Data on biological monitoring of workers exposed to MDA in the United States existed

Physical Properties of Candidate Compounds
The candidate compounds for BEELs were usually solid, high molecular weight (>150), low vapor pressure (<10^-3 mm Hg), low Henry Law constant, high octanol/water partition coefficient (log Kow >1), low water solubility but still somewhat soluble in water (0.01-1 %; MW <500); chemically inert (saturated, polyhalogenated or aromatic compounds); high environmental persistence (resists biodegradation, water leaching and sunlight photodegradation); and toxicological properties concerned with systemic toxic effects rather than just the portal of entry (hepatotoxins, nephrotoxins, hematopoietotoxins, and central nervous system agents). The skin permeability constant varies with skin location, the range being within 3-fold, the range being less for more water soluble chemicals.

MDA Risk Assessment
IARC classifies MDA as a group 2B carcinogen. DECOS (2000) published a risk assessment based on male F344/n rat liver and thyroid tumor data obtained during a 721 exposure day National Toxicology Program study in 1983 with the dihydrochloride salt of MDA administered in drinking water. There was no statistically significant linear dose response but the high absorbed dose of 15 mg/kg/d was statistically different from, and above a signal/noise ratio of 2 relative to control male rat tumor data. The latter dose constituted a rat cancer incidence of 0.085 tumors (mg/kg/d)^-1. Adjusting for workplace exposure conditions (8 h/d, 48 w/y for a 70 kg male), human working lifetime (40 y relative to a lifespan of 75 y) and assuming moderate physical activity (10 m³ breathed in) and exposure only by inhalation, DECOS assigned a tumor incidence of 4.3 x 10^-3 tumors per mg MDA/m³ air or a cancer risk of 4 x 10^-3 for 0.9 mg/m³, using one significant figure.

Liver tumors were shown to be induced on skin exposure of MDA base at a high absorbed dose of 21.3 mg/kg/d in female C3Hf/Bd mice, applied three times a week over 24 months reported by Holland et al in 1987. In common with the oral studies, the dose response was not linear but it was almost so. A risk assessment for mice simlar to the above for rats revealed a tumor rate lower than for male rats exposed by the oral route so that the DECOS risk assessment was more conservative. However, there was no doubt that liver tumors could be induced in mice after skin absorption by MDA. There are no equivalent human data.

ATSDR based its Intermediate Oral Minimal Risk Level (MRL) of 0.08 mg/kg/d on a 12-week study of liver cell degeneration and gastrointestinal effects in Wistar rats from a study published by Pludro et al in 1969, assuming a animal to human uncertainty factor of 10 and also a factor of 10 for human variability. ATSDR also derived an Oral Acute MRL of 0.2 mg/kg from a LOAEL of 25 mg/kg for minimal liver cell necrosis in Sprague Dawley rats found by Bailie et al 1993, using factors of 3 (minimal LOAEL), 10 (animal to human extrapolation), 10 (human variability), and 0.5 (facilitated absorption).

OSHA in its risk assessment estimated that 4.2 mg/d was a no-effect human dose equivalent to 0.060 mg/kg/d or a PEL of 0.08 mg/m³, based on liver cancer.

Thus in terms of the DECOS risk of liver and thyroid tumors, the various regulatory and recommended guidelines have the following liver/thyroid cancer risk:

• OSHA PEL, 0.08 mg/m³: 4 x 10^-4
• NIOSH REL, 0.03 mg/m³: 1 x 10^-4
• ACGIH TLV-TWA, 0.8 mg/m³: 4 x 10^-3
• DECOS TWA: 0.09 mg/m³: 4 x 10^-4
• ATSDR Intermediate MRL, 0.08 mg/kg/d (12 weeks): 5 x 10^-4
• ATSDR Oral Acute MRL (1 day), 0.2 mg/kg: 6 x 10^-3

The risks for the ATSDR MRLs assume that chronic effects would be eventually shown after subacute and acute exposure. This is probably unlikely because cell damage may kill potentially cancerous cells. Nevertheless the approximate agreement of the OSHA PEL and the DECOS TWA with the ATSDR Intermediate MRL cancer equivalent are noteworthy.

The BEEL Committee then applied the biological equivalent approach to obtain that an absorbed dose of 9 mg per work day constituted a cancer risk of 4 x 10^-3 at moderate physical activity (10 m³ of air at 0.9 mg/m³).

MDA is known to be 55% absorbed at a forearm skin coverage of 600 µg/cm² from 10% MDA in ethanol (Bos et al, 1998). If the area of the hands and lower forearms is 2000 cm² (Boogaard and van der Waal, 1994) and skin absorption is the only exposure route, a cancer risk of 4 x 10^-3 is equivalent to a skin coverage of 9,000 µg/2000 cm² = 4.5 µg/cm². At such a low coverage, it is conservative to assume the absorption efficiency of MDA is 100%. At the OSHA PEL equivalent, the skin coverage is thus 0.45 µg/cm². Such recommendations are also applicable to the material permeated through gloves on the side opposite the skin.

MDA produces jaundice in humans (Epping jaundice accident in 1965) on ingestion at doses between 10-30 mg/kg, with jaundice still reversible at a dose of 3 mg/kg. The ATSDR Oral Acute MRL of 0.2 mg/kg should be protective of jaundice and liver damage in humans after acute exposure, and is equivalent to an absorbed dose of 14 mg MDA.

For biological monitoring purposes, urine levels of MDA will reflect input from all routes of exposure. It is known that 8% of MDA appears in a 24-h urine after acute exposure to workers. If 1 L urine contains 1 g creatinine, a cancer risk equivalent to the TLV-TWA corresponds to 720 µg/L or 720 µg/g creatinine in a 24-h urine. Similarly, the urine level corresponding to the DECOS TWA or the OSHA PEL is 72 µg/L or 72 µg/g creatinine in a 24-h urine.

The OSHA format of levels was adopted as the basis of the BEELS: Action levels at 0.5 BEEL with the BEEL set equivalent to the OSHA/DECOS/ATSDR Intermediate MRL recommendations for hand-lower forearm skin coverage/glove permeation (0.45 µg/cm²) and biological monitoring (72 µg/L or 72 µg/g creatinine in a 24-h urine). Medical monitoring for liver damage is recommended at and above the BEEL. The Removal from Exposure BEELs to prevent jaundice and liver damage after a one day exposure are then 7.0 µg/cm² (skin coverage/glove permeation) and 1120 µg/L or 1120 µg/g creatinine in a 24-h urine.

The key question is what is the acceptable risk that can be tolerated since there are about 4,000 workers exposed to MDA in the United States?

References
Agency for Toxic Substance Disease Registry (ATSDR). 1998. Toxicological Profile for Methylenedianiline. ATSDR, Atlanta, GA.

Bailie, M.B., Mullaney, T.P., Roth, R.A. 1993. Characterization of acute 4,4’-methylenedianiline hepatotoxicity in the rat. Environ. Health Perspect. 101: 130-133.

Boogaard, P.J., van der Waal, H. 1994. Biological monitoring of dermal exposure to 4,4’-diamino diphenylmethane (MDA) by determination of MDA in hydrolyzed urine-a human volunteer study. Shell Biomedical Laboratory, preliminary Internal report, 1994.

Bos, P.M.J., Brouwer, D.H., Stevenson, H., Boogaard, P.J., de Kort, W.L.A.M., JJ van Hemmen, J.J. 1998. Proposal for the assessment of quantitative dermal exposure limits in occupational environments: part 1. Development of a concept to derive quantitative dermal occupational exposure limit. Occup Environ Med 55: 795-804.

Dutch Expert Committee on Occupational Standards (DECOS). 2000. 4,4’-Methylene Dianiline: Health Based Calculated Occupational Cancer Risk Values, Health Council of the Netherlands Public. No. 2000/11OSH, The Hague.

Holland, J.M., Smith, L.H., Frome, E., Whitaker, M.J., and Gipson, L.C. 1987. Test of Carcinogenicity in Mouse Skin: Methylenedianiline, -Glycidyloxytrimethyloxysilane, -Aminopropyltriethoxysilane and a Mixture of m-Phenylenediamine, Methylenedianiline, and Diglycidylether of Bisphenol-A, ORNL/TM-10472. Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN Holland, J.M., Smith, L.H., Frome, E., Whitaker, M.J., and Gipson, L.C. 1987. Test of Carcinogenicity in Mouse Skin: Methylenedianiline, -Glycidyloxytri-methyloxysilane, -Aminopropyltriethoxysilane and a Mixture of m-Phenylenediamine, Methylenedianiline, and Diglycidylether of Bisphenol-A, ORNL/TM-10472. Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN

International Agency for Research on Cancer (IARC). 1986. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some Chemicals used in Plastics and Elastomers, Vol 39. IARC, World Health Organization, Lyon, France. pp. 347-365.

National Toxicology Program (NTP). 1983. Carcinogenesis Studies of 4,4-Methylenedianiline Dihydrochloride (CAS No 13552-44-8) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies), Technical Report series Vol. 248, Research Triangle Park, NC.

OSHA. 2000. US Code of Federal Regulations, Title 40, Part 1910.1050. USGPO, Washington, DC. July, 2000.

Pludro, G., Karlowski, K., Mankowska, M. et al. 1969. Toxicological and chemical studies of some epoxy resins and hardeners. I. Determination of acute and subacute toxicity of phthalic acid anhydride, 4,4’-diaminophenylmethane and of the epoxy resin: Epilox EG-34. Acta Pol. Pharm. 26: 352-357.