July 21, 2009

Science Advisory Board Meeting Minutes
DEP, 2nd Floor
July 21, 2009

SAB Members present: Larry Boise (Vice Chair), Chris Swartz, Hilary Hackbart, Lorraine Braunsdorf, David Williams (Chair), Anne Marie Desmarais, Veronica Vieira

Others present: Heather Tenney (TURI), John Fischer (DEP on behalf of Glenn Keith), Liz Harriman (TURI), Mary Butow (TURI), John Raschko (OTA), Dave Wawer (MCTA), Sanford Ostroy (retired professor, Purdue University), Jack Paul (Hubbard Hall), Jeffrey Davis (Hubbard Hall), Mark Stelljes, PhD (SLR International Corporation – on behalf of Envirotech International), Rich Morford (Envirotech International), Mark Smith (DEP Office of Research and Standards), Rich Bizzozero (OTA)

Welcome

Program Updates
The TURA program budget is in very tough shape. The Conference Committee rolled the TURI budget into the general UMASS System budget. Currently, OTA is at 40% of FY2009 budget, DEP 80% of their FY2009 budget and TURI has no established budget. Efforts within the legislature by both representatives and senators to put in a supplemental amount specifically for TURI are well under way, but it is uncertain as to when the results of those efforts will be known. The University is currently committed to supporting TURI staff for a few months. There have been a few layoffs to date. Staff are also pursuing outside funding.

The Administrative Council meeting is next week, July 29th, 9AM. There are no Board or Council meetings scheduled for August. Meetings will resume in September.

Approve June Minutes
A motion was put forth to approve the June meeting minutes. The motion was unanimously approved.

nPB
Discussion was continued from last month’s meeting. DEP has requested to have this substance added to the TURA list. It was noted that it has surfaced as a potential alternative to the HHS perchloroethylene. The issue of adding it to the list has also been raised by the Administrative Council and the Advisory Committee.
There was a review of data and a discussion of areas of concern from the June meeting:

· PBT – rapidly hydrolyzes – not persistent
· IARC – no monograph
· Repro/Developmental – identified in previous minutes; Prop 65; NTP document; various other studies.
· Mutagen – 17 negative – one paper suggests weak mutagen (Toraason).
· LD50 – relatively high
· TLV – 10ppm
· Neurotoxicity – CNS depressant

Reproductive toxicity and neurotoxicity were determined to be the key issues surrounding listing.

Clarification: n-propyl bromide is a casual synonym for 1-bromopropane, with 2-bromopropane as a minor contaminant. All information distributed for this meeting was for 1-bromopropane, CAS #106-94-5. There also exists information on 2-bromopropane, but it has not been considered at this point. Note regarding iPB contamination: Today’s nPB is at .01 or less iPB content. None is above .01% - which is better than ASTM standard used for solvents. Industry has independently reduced iPB content. All the testing toxicity and tox reports were likely done with nPB with much higher (1-2%) iPB content.

A summary of the large NTP monograph file identifying reproductive and developmental concerns was distributed. It was noted that many other sources reference this document, i.e. CA Prop 65 list. An SAB member noted that the panel determined no exposure effects at exposure concentrations below 100ppm. TURA Program staff further noted that the final statement in the report was serious concern at exposures ranging from 18-331ppm. There was minimal concern at lower exposures ranging from .04-.6 ppm. Other studies indicated that 250 ppm is a very common exposure. Acknowledging this big range, an SAB member also located several studies that show reproductive effects in various forms, including but not limited to:

• Neurotransmitter study at 50ppm. (Suda et al, 2008).

• Second generation reproductive study (Wood). (Mark Stelljes noted that research was unable to confirm that study.)

• Exposure study – different adhesive sprayers with a wide range of exposure concentrations (10-100s ppm).

Information from industry guests was then distributed. There are approximately 150 published/unpublished studies on nPB according to Envirotech. Documents they distributed were:

• Hasspieler et al: Toxicological assessment of industrial solvent using human cell bioassays: assessment of short-term cytotoxicity
• Stelljes & Wood: Development of an occupational exposure limit for nPB using benchmark dose methods (10 years of knowledge into one document)
• SLR Memorandum – written in 2006 – 7/21/09 – previously an internal document – will likely be in Annual Reviews of Toxicology- Mark Stelljes’s interpretation of NTP toxico-kinetic data and disposition

Mark Stelljes gave a five minute overview of the reproductive and neurotoxic concerns with regard to nPB based on his research. He has been working on it since 2000. He wrote the first benchmark dose analysis review of nPB. He took all of the studies with raw data in the literature and evaluated them using benchmark dose analysis to evaluate every endpoint with acceptable data. The two primary drivers for this in depth research were reproductive and neurological effects. The most sensitive endpoint in the study was reduced sperm motility in the F1 (first offspring) generation in a second generational study at 159 ppm BMD (Bench Mark Dose).

Key issues of note (as noted by Mark Stelljes):
· Further reproductive notes – there are several human exposure cases; however there are too few cases to draw an epidemiological conclusion.
· TCE – rats/mice metabolize the same chemical differently through MFO (Mixed Function Oxidase) – basically the same enzyme system that works on phase 1 reactions for nPB glutathione (GSH) conjugation.
· Based on similarities in metabolism between TCE and nPB it can be inferred that humans are no more sensitive to nPB than TCE.
· There is no doubt that nPB can cause reproductive toxicity – the question is at what concentration is that going to be an issue in humans
· Info from CERHR – animal studies – 100 ppm is the de minimus level for reproductive toxicity.
· <100 ppm is likely to be protective for reproductive toxicity for humans.
· Thought CERHR report captured the state of toxicity well.
· The Garner study came out in 2005 well after the NTP study and the monograph was written. New information supports what Garner found.
· DBCP(dibromochloropropane) has visceral halogens – way different from metabolization - enough structural dissimilarity
· Mark Stelljes’ paper on the BMD (Bench Mark Dose) is peer reviewed and published. TERA didn’t do the full benchmark dose. US EPA did a BMD study which concurred with the 168ppm. (Fed Register)
· In case studies where humans were exposed and toxicity has resulted – every case has been through the spray adhesive sector.
· 1st degreasing use in 1999 – 2001; NIOSH came in and got levels of 398 ppm in the workplace- there was no ventilation. Also there was a very large dermal absorption of the chemical from spraying all over the foam cushions.
· Work in CA – recommending skin notation. There is substantial exposure via dermal.
· TLV documentation – there is no have skin notation. There is very set criteria for that.
· They have not found sensitizer information on the chemical. There may be some European tests on that - Envirotech will check and find out. Some testing is now being released from the companies.
· Up to 2006 – Arkansas Albemarle Corporation opened a plant to produce nPB – all other nPB is imported from Israel and China.
· Considerations under EPA SNAP program
· Considered SNAP for vapor degreasing.
· Likely EPA has proposed an unacceptable finding for use in aerosol sprays and adhesives, coatings, and inks – this unacceptable finding will probably be changed to acceptable based on info.
· EPA will finalize the SNAP designation for adhesives, coatings and inks sometime this year.
· Is EPA looking at this with regard to 313 listing (TRI)? EPA hasn’t looked at TRI listing for a long time. The only things EPA is currently finalizing are the two SNAP proposals and a petition to be exempted from definition as a VOC.
· nPB will be in front of the DART (Developmental and Reproductive Toxicity) committee in CA – petition to have it de-listed as a developmental toxin. nPB got on their list due to the NTP study – under their authoritative provision. The studies they use do show developmental toxicity. Since then information has come out to clear that up. Envirotech says there is no study to say there is developmental toxicity. However, in Huntington 2001 the author’s noted a change in fetal body weights at 100ppm. In the next paragraph they say it wasn’t dose related but due to the change in the time of day when they were weighed. The difference was completely explained by the timing when they weighed the animals. That was the endpoint/study that ACGIH used to call it developmental (EPA Federal Register 2007). The difference in body weights correlates with historical growth.

One of the concerns driving the potential listing is the use of the chemical in dry cleaning. Use is as a drop in for Perc in 3rd generation and newer Perc machines. There is a cost of about $5K to convert the machine to use ‘Drysolv’. It is being used in CA. There was about 7 years of R & D for product. It has been on the market for 2 years. It is 5 times more expensive than Perc and boils at much lower temp. There is much less electricity involved and it cuts running time in the Perc machine by about 45%.
There were a number of ambient emission and exposure tests in CA. Canisters were placed at 7 locations in Sacramento during normal operations. One of the canisters was placed directly outside the basket. It was placed there to capture the worst case sample when the machine was opened. The highest concentration was 9.8ppm at the drum exit. That is with a 3rd generation machine. Older type machines couldn’t use the product.

In terms of Massachusetts, Jeff from Hubbard Hall gave a quick overview of users. Many companies use far less than 10,000 lbs. 1,000 lbs is 2 drums a year. They have 141 nPB customers in New England – 60% of those are in MA. A typical user uses 1 to 10 drums a year.

At this point there was a clarification of the listing and categorization processes. An addition to the list is dependent on the chemical itself - consider health and environmental effects of the substance regardless of the actual workplace exposure – the intrinsic hazard of chemical.
Mark Stelljes: from hazard perspective it should be listed but as low priority.
There is no denying nPB is a CNS depressant. We know that from the cases at a high exposure. Neurological damage seen is very consistent with bromism. Circulating levels of bromine are a good biomarker for exposure to nPB. There was general agreement that nPB is a CNS depressant and a reproductive toxicant at some level – disagreement is around whether that level is likely to exist in the workplace.

All agree with the NTP study – nPB is a CNS Depressant. At 250ppm there is a serious concern. Areas of disagreement are outside of the realm of the SAB (workplace exposure – policy concern).

There was a motion to list nPB and review as a potential lower hazard chem. After review of information distributed today, consider categorizing at a subsequent meeting.

Discussion:

If 2 individual CAS numbers are listed the reporting threshold would be for 10K lbs for each. If they were HHS the reporting threshold would be 1K lbs for each. We could potentially streamline things for companies – with the group of bromopropanes. However, that could make it more difficult to divide up to more/less hazardous categories. It is possible that nPB will receive a less hazardous categorization. Different from 2-bromopropane – industry would recommend 2-bromopropane going to high immediately. There was some concern expressed with quality (contamination) out of China.

There was a Motion to list nPB and discuss categorization upon the review of information from Envirotech. 7 members voted in favor, none opposed or abstaining.

Guidelines Discussion

Anne Marie prepared a draft Guideline document and distributed it to the group.
It has tiered levels of info (listed below) in order of importance. If there is info in the top tiers then we can have much more confidence in making the decisions. When the info in the top tiers is missing, certainty is less.

1st tier – PBT list – also include repro/dev, endocrine disruption
2nd tier – known or suspected carcinogen
3rd tier – known toxic effects –RfD
4th tier – Sensitizers and allergens (Y/N)
5th tier – acute toxicity in both humans and wildlife
6th tier – other toxicity info(MRLs, REL, TLV)
7th tier – physical properties
8th tier – SAR

Some of these are idiosyncratic effects – apart from classical effects. Some are specific sensitizers to certain populations. When evaluating information, note source/quality of study/peer review, etc. All data not created equally – how do we look at what we have the most confidence in? A lot has to do with people’s judgment and priorities. Ideally this is addressed with the DELPHI method – many people with different perspectives weighing in.
The process goes in to deciding the tiers. If each member has input into the levels – the prejudices/bias would come out. We should discuss that, once we have agreed on the hierarchy of importance of the data. There was some concern that people will look at this and say it is beginnings of an algorithm – therefore we must develop it further. It is better to phrase it as using the expert judgment method – these are the things we are considering in a tier approach. For instance, we had a rule if something is an IARC 1, we don’t need to spend time talking about it – we just put it in. We should document and explain this as part of explaining the expert approach.

We want to organize/systematize – not write a rule – a confidence tool.

Email comments to Anne Marie and cc: Heather – by September 9th.

Next Meeting
Wednesday, September 16, 2009 1:30pm – Reminder – Lunch will not be provided

Addendum of articles submitted by SAB/Industry for Review:
Submitted by SAB Member, Chris Swartz:

1) Cheever, KL (Cheever, K. L.); Marlow, KL (Marlow, K. L.); B'Hymer, C (B'Hymer, C.); Hanley, KW (Hanley, K. W.); Lynch, DW (Lynch, D. W.)
“Development of an HPLC-MS procedure for the quantification of N-acetyl-S-(n-propyl)-L-cysteine, the major urinary metabolite of 1-bromopropane in human urine”
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 877 (8-9): 827-832 MAR 15 2009

2) Huang, F (Huang, Fen); Ning, H (Ning, Huan); Xin, QQ (Xin, Qian-Qian); Huang, Y (Huang, Yong); Wang, H (Wang, Hua); Zhang, ZH (Zhang, Zhi-Hua); Xu, DX (Xu, De-Xiang); Ichihara, G (Ichihara, Gaku); Ye, DQ (Ye, Dong-Qing)
“Melatonin pretreatment attenuates 2-bromopropane-induced testicular toxicity in rats”
TOXICOLOGY, 256 (1-2): 75-82 FEB 4 2009

3) Suda, M (Suda, Megumi); Honma, T (Honma, Takeshi); Miyagawa, M (Miyagawa, Muneyuki); Wang, RS (Wang, Rui-Sheng)
“Alteration of brain levels of neurotransmitters and amino acids in male F344 rats induced by three-week repeated inhalation exposure to 1-bromopropane”
INDUSTRIAL HEALTH, 46 (4): 348-359 JUL 2008

4) Perrone, J (Perrone, J.); Mazer, M (Mazer, M.); DeRoos, FJ (DeRoos, F. J.)
“Encephalopathy and peripheral neuropathy secondary to 1-bromopropane toxicity”
CLINICAL TOXICOLOGY, 46 (5): 417-417 307 JUN 2008

5) Banu, S (Banu, Shameema); Ichihara, S (Ichihara, Sahoko); Huang, F (Huang, Fen); Ito, H (Ito, Hidenori); Inaguma, Y (Inaguma, Yutaka); Furuhashi, K (Furuhashi, Koichi); Fukunaga, Y (Fukunaga, Yoshinobu); Wang, Q (Wang, Qiangyi); Kitoh, J (Kitoh, Junzoh); Ando, H (Ando, Hisao); Kikkawa, F (Kikkawa, Fumitaka); Ichihara, G (Ichihara, Gaku)
“Reversibility of the adverse effects of 1-bromopropane exposure in rats”
TOXICOLOGICAL SCIENCES, 100 (2): 504-512 DEC 2007

6) Raymond, LW (Raymond, Lawrence W.); Ford, MD (Ford, Marsha D.)
“Severe illness in furniture makers using a new glue: 1-bromopropane toxicity confounded by arsenic”
JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE, 49 (9): 1009-1019 SEP 2007

7) Garner, CE (Garner, C. Edwin); Sloan, C (Sloan, C.); Sumner, SCJ (Sumner, S. C. J.); Burgess, J (Burgess, J.); Davis, J (Davis, J.); Etheridge, A (Etheridge, A.); Parham, A (Parham, A.); Ghanayem, BI (Ghanayem, B. I.)
“CYP2E1-catalyzed oxidation contributes to the sperm toxicity of 1-bromopropane in mice”
BIOLOGY OF REPRODUCTION, 76 (3): 496-505 MAR 2007

8) Kim, YJ (Kim, Youn-Jung); Ryu, JC (Ryu, Jae-Chun)
“Evaluation of the genetic toxicity of synthetic chemicals (XIV)-in vitro chromosomal aberration assay with 11 chemicals in Chinese hamster lung cells”
MOLECULAR & CELLULAR TOXICOLOGY, 2 (2): 89-96 JUN 30 2006

9) Hanley, KW (Hanley, K. W.); Petersen, M (Petersen, M.); Curwin, BD (Curwin, B. D.); Sanderson, WT (Sanderson, W. T.)
“Urinary bromide and breathing zone concentrations of 1-bromopropane from workers exposed to flexible foam spray adhesives”
ANNALS OF OCCUPATIONAL HYGIENE, 50 (6): 599-607 AUG 2006

10) Furuhashi, K (Furuhashi, Koichi); Kitoh, J (Kitoh, Junzoh); Tsukamura, H (Tsukamura, Hiroko); Maeda, K (Maeda, Kei-ichiro); Wang, HL (Wang, Hailan); Li, WH (Li, Weihua); Ichihara, S (Ichihara, Sahoko); Nakajima, T (Nakajima, Tamie); Ichihara, G (Ichihara, Gaku)
“Effects of exposure of rat dams to 1-bromopropane during pregnancy and lactation on growth and sexual maturation of their offspring”
TOXICOLOGY, 224 (3): 219-228 JUL 25 2006

11) Toraason, M; Lynch, DW; DeBord, DG; Singh, N; Krieg, E; Butler, MA; Toennis, CA; Nemhauser, JB
“DNA damage in leukocytes of workers occupationally exposed to 1-bromopropane”
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, 603 (1): 1-14 JAN 31 2006

12) Ichihara, G
“Neuro-reproductive toxicities of 1-bromopropane and 2-bromopropane”
INTERNATIONAL ARCHIVES OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH, 78 (2): 79-96 MAR 2005

13) Raymond, LW; Ford, MD
“Toxicity of the new solvent, 1-bromopropane: What is the role of arsenic?”
JOURNAL OF INVESTIGATIVE MEDICINE, 53 (2): S401-S401 MAR 2005

14) Ichihara, G; Li, WH; Shibata, E; Ding, XC; Wang, HL; Liang, YD; Peng, SM; Itohara, S; Kamijima, M; Fan, QY; Zhang, YH; Zhong, EH; Wu, XY; Valentine, WM; Takeuchi, Y
“Neurologic abnormalities in workers of a 1-bromopropane factory”
ENVIRONMENTAL HEALTH PERSPECTIVES, 112 (13): 1319-1325 SEP 2004

15) [Anon]
“NTP-CERHR expert panel report on the reproductive and developmental toxicity of 1-bromopropane - Center for the evaluation of risks to human reproduction”
REPRODUCTIVE TOXICOLOGY, 18 (2): 157-188 MAR-APR 2004

16) Ichihara, G; Li, WH; Ding, XC; Peng, SM; Yu, XZ; Shibata, E; Yamada, T; Wang, HL; Itohara, S; Kanno, S; Sakai, K; Ito, H; Kanefusa, K; Takeuchi, Y
“A survey on exposure level, health status, and biomarkers in workers exposed to 1-bromopropane”
AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, 45 (1): 63-75 JAN 2004

17) Honma, T; Suda, M; Miyagawa, M
“Inhalation of 1-bromopropane causes excitation in the central nervous system of male F344 rats”
NEUROTOXICOLOGY, 24 (4-5): 563-575 AUG 2003

18) Yamada, T; Ichihara, G; Wang, HL; Yu, XZ; Maeda, K; Tsukamura, H; Kamijima, M; Nakajima, T; Takeuchi, Y
“Exposure to 1-bromopropane causes ovarian dysfunction in rats”
TOXICOLOGICAL SCIENCES, 71 (1): 96-103 JAN 2003

19) Sohn, YK; Suh, JS; Kim, JW; Seo, HH; Kim, JY; Kim, HY; Lee, JY; Lee, SB; Han, JH; Lee, YM; Lee, JY
“A histopathologic study of the nervous system after inhalation exposure of 1-bromopropane in rat”
TOXICOLOGY LETTERS, 131 (3): 195-201 MAY 28 2002

20) Sekiguchi, S; Suda, M; Zhai, YL; Honma, T
“Effects of 1-bromopropane, 2-bromopropane, and 1,2-dichloropropane on the estrous cycle and ovulation in F344 rats”
TOXICOLOGY LETTERS, 126 (1): 41-49 JAN 5 2002

21) Yu, XZ; Ichihara, G; Kitoh, J; Xie, ZL; Shibata, E; Kamijima, M; Takeuchi, Y
“Neurotoxicity of 2-bromopropane and 1-bromopropane, alternative solvents for chlorofluorocarbons”
ENVIRONMENTAL RESEARCH, 85 (1): 48-52 JAN 2001

22) Ichihara, G; Kitoh, J; Yu, XZ; Asaeda, N; Iwai, H; Kumazawa, T; Shibata, E; Yamada, T; Wang, HL; Xie, ZL; Takeuchi, Y
“1-bromopropane, an alternative to ozone layer depleting solvents, is dose-dependently neurotoxic to rats in long-term inhalation exposure”
TOXICOLOGICAL SCIENCES, 55 (1): 116-123 MAY 2000

23) Ichihara, G; Yu, XZ; Kitoh, J; Asaeda, N; Kumazawa, T; Iwai, H; Shibata, E; Yamada, T; Wang, HL; Xie, ZL; Maeda, K; Tsukamura, H; Takeuchi, Y
“Reproductive toxicity of 1-bromoprapane, a newly introduced alternative to ozone layer depleting solvents, in male rats”
TOXICOLOGICAL SCIENCES, 54 (2): 416-423 APR 2000

24) Kim, HY; Chung, YH; Jeong, JH; Lee, YM; Sur, GS; Kang, SK
“Acute and repeated inhalation toxicity of 1-bromopropane in SD rats”
JOURNAL OF OCCUPATIONAL HEALTH, 41 (2): 121-128 APR 1999

25) Zhao, WY; Aoki, K; Xie, TX; Misumi, J
“Electrophysiological changes induced by different doses of 1-bromopropane and 2-bromopropane”
JOURNAL OF OCCUPATIONAL HEALTH, 41 (1): 1-7 JAN 1999

26) Yu, XZ; Ichihara, G; Kitoh, J; Xie, ZL; Shibata, E; Kamijima, M; Asaeda, N; Takeuchi, Y
“Preliminary report on the neurotoxicity of 1-bromopropane, an alternative solvent for chlorofluorocarbons”
JOURNAL OF OCCUPATIONAL HEALTH, 40 (3): 234-235 JUL 1998

Submitted for review by Mike Ellenbecker, TURI:
30. Park JS; Kim Y; Park DW; et al: An outbreak of hemaotpoetic and reproductive disorders due to
solvents containing 2-bromopropane in an electronic factory, South Korea: epidemiological survey. J OccupHealth 39:138.143 (1997).

43. Kim Y; Jung K; Hwang T; et al.: Hematopoietic and reproductive hazards of Korean electronic workers
exposed to solvents containing 2-bromopropane. Scand J Work Environ Health 22:387.391 (1996).

44. Takeuchi Y; Ichihara G; Kamijima M: A review on toxicity of 2-bromopropane: mainly on its reproductive toxicity. J Occup Health 39:179.191 (1997).

46. Ichihara G; Ding X; Yu X; et al.: Occupational health survey on workers exposed to 2-bromopropane at low concentrations. Am J Ind. Med 35:523.531 (1999).

Submitted by Industry Representatives:
1) Maier A; Dourson M; Zhao J; Hack E. “Scientific Review of 1-Bromopropane Occupational Exposure Limit Derivations – Preliminary Thoughts and Areas for Further Analysis” Toxicology Excellence for Risk Assessment, August 2004

2) Stelljes M. “Mechanistic Hypothesis for n-Propylbromide and Ramifications for Occupational Exposure Limit in the United States”
SLR International Corporation Memorandum, July 21, 2009

3) Hasspieler B, Haffner D, Stelljes M, Adeli K. “Toxicological assessment of industrial solvents using human cell bioassays: assessment of short-term cytotoxicity and long-term genotoxicity potential” Toxicology and Industrial Health 2006; 22: 301-315

4) Stelljes M, Wood R. “Development of an occupational exposure limit for n-Propylbromide using benchmark dose m