2003 William P. Yant Award presentation
Exposure assessment, health
hazard evaluation, and control
of ethylene glycol ethers
Tung-Sheng Shih, Sc.D.
Institute of Occupational Safety and Health,
Council of Labor Affairs, Executive Yuan,
Taiwan, Republic of China
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Introduction of EGEs
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ROCH2CH2OH, highly lipid and water soluble
Widely used (24,000 tons in 2002) in Taiwan
EGEs!ROCH2COH!ROCH2COOH (AAAs)
AAAs are the proximate toxicants of EGEs
Toxicity: 2-methoxy ethanol (ME) > EE > BE
Highly skin permeable, low skin irritating and
sensitizing effects, with very mild odor
• Strong adverse effects from animal studies
• Many intoxication cases have been reported
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Chronicles of concerns on EGEs
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1984/1994: US NIOSH held two Int’l symposia
1985: UK HSE published toxicity review
1990: WHO published health criteria 115
1990/1991: NIOSH published criteria of stds
1992: US ACGIH & German DFG set BEI for EE
1993: US OSHA proposed new PELs for ME/EE
1995: ACGIH put ME in BEI list with Nq notation
1999: Taiwan OSHA set new PELs for EGEs
2002: Taiwan put EGEs in mandatory monitoring
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Research Design
Exposure assessment
EM method
BM method
Skin chamber Exp. survey
detergent
MAA accumulation
Issues to be resolved:
Need better methods
Limited human data on
exposure and internal dose
MAA in urine,
plasma, saliva
Suggest BEI
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Passive badges to measure ME
• Good agreement with charcoal tubes: r=0.992
" Good precision: intraclass r=0.994
" Minimal interference by co-exposures of
solvents and environmental factors (T/RH)
!Small, light, easy of operation, low cost
!Become IOSH recommended EM method
- Int Arch Occup Environ Health, 2000
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GC/MS method to measure MAA
• Urine + HCl ! MC/IPA ! GC/MS
" Good agreement with refer. method: r=0.999
" The only method that allows concurrent
measurement of EGEs and AAAs in different
bio-samples (urine, blood, saliva, semen)
$No derivertization, safe, rapid, accurate,
precise, simple, low cost, sensitive, specific
$Become IOSH recommended BM method
- Occup Environ Med, 1999; Chromatographia, 2001
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New chamber to measure
skin uptake of vapors
Arch Environ Health, 2000
J Occup Environ Med, 2000
US and ROC patents, 1999
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Flash evaporator
SnO2 sensors
Fans
25 or 300
ppm ME
auto micro
syringe
T/RH
aluminum foil and
3M elastic bandage
cold trap
(water bath)
SnO2 sensor
temperature/
personal
humidity sensor
pump
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R H(% )
T ( ¢ J)
$Fully automatic and good control in T/RH/Conc.
$Skin uptake of vapor is close to that via inhalation
$Much higher than other solvents with skin notation
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Survey of EGEs (%) in detergents
• EGEs were widely used in detergents
• Contents of EGEs: 1.2-16% (n=32)
• EGEs (%) are highest in the range cleaners
• EGEs were usually not labeled in products
$Manufacturers develop less toxic formula
$Provide education to prevent skin contact
- J Occup Safety Health, 1999 (in Chinese)
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Priority setting from nationwide survey
• Paints (EE/EEAc/BE): 13% > PEL, n=62
• Spray painting (EEAc/BE): 0% > PEL, n=50
• Copper laminate circuit board (CLCB industry,
ME): 38% > PEL, n=310
• Silk-screening (EE/EEAc): 39% > PEL, n=98
!Choose these two high exposure industries
for in-depth follow-up studies
- J Occup Safety Health, 1998 (in Chinese)
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Accumulation of internal dose
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mean daily MAA, mg/g crt
• The mean urinary MAA
increased over a work
week for 18 workers
even though their
mean daily exposure
levels were very
consistent.
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day
- Arch Environ Health, 2001
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Recommendation of BEI of ME
• No BEI due to insufficient human data: ACGIH
• Good correlation was found between the Friday
post-shift urinary MAA (or the weekly increase
of urinary MAA) and the weekly mean exposure
to ME (r > 0.7)
!Suggested BEI: Friday post-shift urinary MAA
(40 mg/g crt) for 5 ppm (PEL) weekly mean
exposure of ME
- Occup. Environ Med, 1999
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Different biomarkers of ME
" Close correlation among MAAplasma, MAAurine,
and MAAsaliva (r > 0.896)
" Levels of MAAsaliva (only 1/30 of MAAurine)
represents free and active fractions
" When high levels of MAAsaliva were observed,
an effective surrogate for over exposure of
ME, immediate control strategy should be
implemented
" MAAplasma is a useful marker for toxicokinetics
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MAA is a good biomarker of ME
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MAA is the major toxic metabolite of ME
MAA can be easily measured
Half-life of MAA is long
Urine sample is easy to collect
Dose-response relationship exists, may
reflect the active agent in target sites and
integrated exposures
• No background for non-exposed humans
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Research Design
Health hazards
Reprod.
Hema., liver, SCE
kidney, neuro.
Recovery
Exposure assessment
EM method BM method
Skin chamber Exp. survey detergent
MAA accumulation
Issues:
Limited human epidemiological
data on ME-related health effects
MAA in urine,
plasma, saliva
Suggest BEI
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Health hazards evaluation
• Significantly lower levels of Hgb, Hct, and RBC
found in exposed male workers (26%, n=46)
than in control (3%, n=93)
• No differences found in other health effects
(liver, kidney, neurological, reproductive, SCE)
• Dose-response relationship exists between
exposure of ME or urinary MAA and
hematological effect
!Hematological effect is the most sensitive health
hazard of ME
- Occup Environ Med, 2000
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Recovery of hematological effect
29 exposed workers: Feb
April
Aug
• Abnormal (%):
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• ME (ppm):
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2.7
0.6
• MAA (mg/g crt):
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!The adverse ME-related hematological
effects could be quickly improved when
exposure is reduced/removed
- Occup Environ Med, 2003
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Research Design
Health hazards
Exposure assessment
Reprod. Hema., liver, SCE
kidney, neuro.
Recovery
EM method BM method
Skin chamber Exp survey detergent
Control measures Follow-up survey accumulation
OHM Eng. control Substitution
Issues:
Lack of effective control
measures
MAA in urine,
plasma, saliva
Revise regulation Suggest BEI
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Horizontal coating line
of CLCB industry
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After improvement
bottom hood
aluminum door
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Vertical coating line
Before: mean=900 ppm
After: mean=27 ppm
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Occupational Health Management
!Good occup. health management is critical
" Clean up the spilled glue
" Replace the cotton gloves with rubber gloves
" Wear respirators in high exposure operations
" Conduct periodical exposure monitoring,
health examination, check-up of ventilation
" Enhance training and education for workers
" Set up the exposure and medical data bases
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Reduction of ME in CLCB industry
" Before improvement:
− mean=38 ppm (n=310), 38% > PEL
− mixing (690 ppm), cleaning (155 ppm)
" After improvement:
− mean=2.7 ppm (n=60), 5% > PEL
$Exposure was effectively reduced
$Technically and economically feasible new
PEL (5 ppm) was proposed to CLA
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Revision of regulations
• EGEs were put into the list of mandatory
exposure monitoring chemicals
• Revision of PELs
– ME and MEAc: PEL reduced from 25 ppm
to 5 ppm
– EE and EEAc: PEL reduced from 25 ppm
to 5 ppm
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Substitution of EGEs
• The annual consumption of EGEs has been
dramatically reduced since 1997
• EGEs are no longer produced in Taiwan
• EGEs have mainly been substituted by the
“less toxic” PGEs
$Proposed new research projects for PGEs
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Research Design
Toxicokinetics
Liquid
Vapor
Human
chamber study
Health hazards
Reprod. Hema., liver, SCE
kidney, neuro.
Recovery
Exposure assessment
EM method BM method
Skin chamber Exp. survey detergent
Control measures Follow-up survey accumulation
Field studies
OHM Eng. control Substitution
Revise regulation
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MAA in urine,
plasma, saliva
Suggest BEI
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4-finger contact with pure 2-ME
fan
Aluminum foil
Cotton finger glove
ME
T/RH sensor
MTI GC
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Skin uptake of ME in humans
" Human skin uptake rate of ME
- In vivo: 8.06 mg/cm2/hr
- In vitro: 1.66; 2.82 mg/cm2/hr (Dugard; Walker)
" Human skin uptake doses of ME
- 5 min 4-finger liquid contact: 109 mg
- 8-hr 5 ppm inhalation: 39 mg (Groeseneken)
- 8-hr 5 ppm whole body skin exposure: 33 mg
$Skin contact should be effectively prevented
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Difference in species in metabolism
" ME is more toxic for humans than animals
− t1/2 of MAA in humans (100 hr) is much
longer than in animals (6-20 hr)
− Conversion of toxic MAA in humans (85%)
is much higher than in animals (34-60%)
− Diff. metabolic pathways: high conjugation
of ME/MAA; ME ! EG found in animals
$Cautions should be taken in extrapolating
findings from animal data to humans
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Metabolites of EG
Additional metabolic
pathways of ME in animals
ME sulphate
H-OCH2CH2OH ME glucuronide MAA glycine
CO2
-------------------------------------------------------------------H3C-OCH2CH2OH (ME) -oxid-> H3C-OCH2COOH (MAA)
Major metabolic pathway of ME in humans
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Consistency in chamber & field studies
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Human chamber study
long t1/2 of MAA
major metabolite: MAA
short t1/2 of ME
minor metabolite: ME
no MAA before exposure
MAA: good association
among diff. biomarkers
" highly skin permeable
" no ME/MAA conjugation
" Field findings
$accumulation of MAA
$high concentration
$no accumulation
$low concentration
$no background MAA
$same association
found in workers
$>> inhalation only
$same in workers
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Exposure assessment and health
hazard evaluation of 2-ethoxy
ethanol acetate (EEAc) in
silk-screening plants
Occup Environ Med, 2003
J Occup Environ Med (submitted)
Ann Occup Hyg (submitted)
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Research of EEAc
" Good agreement between passive badge and
charcoal tubes (r=0.987), minimal interference
" Significantly lower Hgb and Hct were found in
exposed female workers than in controls
" Dose response relationship exists
" Mean exposure reduced from 45 to 5 ppm
" Follow-up survey on health recovery is on going
$Hematological effect is the most sensitive health
hazard of EEAc
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Research of EEAc (cont.)
" Accumulation of urinary EAA over a workweek
" The Friday post-shift urinary EAA is closely corr.
with weekly mean exposure to EEAc (r > 0.9)
" No EAA was found for non-exposed workers
" EEAc was found in post-shift but not next day
!EAA is a good and specific biomarker of EEAc
!Suggested BEI: Friday post-shift EAA (60 mg/g
crt) for 5 ppm weekly mean exposure of EEAc
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Summary of finished researches
Toxicokinetics
Liquid
Health hazards
Vapor Reprod
Human
chamber study
Exposure assessment
Hema. liver, SCE EM method BM method
kidney, neuro.
Recovery
Skin chamber Exp. survey detergent
Control measures Follow-up survey accumulation
Field studies
OHM Eng. control Substitution
MAA in urine,
plasma, saliva
Revise regulation Suggest BEI
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Integration of research and
administrative management
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Integration of resources
• Governmental agencies:
- OSHA/CLA: emphasis inspection program,
new standards development
- BOI/MOE: advancement of manufacturing
processes
- EPA: waste recycle and reduction
- MOH: health promotion
• Research institutes: IOSH/ITRI/academics
- Consultation (tech and information support)
- Nationwide and follow-up surveys
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Integration of resources (cont.)
" Enterprises:
- Employers: policy and financial support
- Industrial hygienists: exposure assessment,
occupational health management program
- Occupational physicians/nurses: physical
examination and health promotion
- Workers/foremen: training and education
- Labor union: progress auditing
- Engineers: control, less toxic raw materials
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Incentives of improvement
" Economic incentives:
- Less citation due to air pollution (EPA) and
exposures of VOC and noise (OSHA)
- More solvents recycled, energy saved, and
rewards for waste reduction (EPA, MOE)
- Free consultation and low interest loan for
monitoring and control (CLA, MOE)
" Good business image:
- Experience sharing on TV and newspapers
- Awards for successful improvement
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Conclusions
" Laboratory chamber experiments coupled
with intensive field surveys provide us better
understanding to the exposures, health
hazards, toxicokinetics, and control of EGEs.
" In addition to better protection of workers’
health and consideration given to technical
and economical feasibility, the results of our
studies provide a better scientific basis for
occup. health regulation setting of EGEs.
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Conclusions (cont.)
" The integrated efforts from government
agencies, research institutes, enterprises, and
labor unions effectively reduced the exposure
of EGEs in Taiwan.
" Current PEL (5 ppm), even the US OSHA
proposed new PEL (0.1 ppm), can not protect
workers’ health without effective prevention of
skin exposures.
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Conclusions (cont.)
• Similar approach has been actively applied to
the investigation of other hazardous
chemicals such as 1,3-butadiene, PGEs,
CS2, TDI, DMF, PAH, Pb, EO, benzene etc.
in Taiwan.
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IOSH
Office building
Research building
Training building
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Thanks
• The recognition of William P. Yant Award
• Dr. Thomas J. Smith; Dr. Robert Herrick
• Dr. Ming J. W. Chang, Dr. Saou-Hsing Liou,
Dr. Ho-Yuan Chang, Dr. Peng-Yau Wang
• Colleagues at the IOSH in Taiwan
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Thank you for your attention
Tung-Sheng Shih, Sc.D.
Institute of Occupational Safety and Health,
Council of Labor Affairs, Executive Yuan,
Taiwan, Republic of China
E mail: stone@mail.iosh.gov.tw
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