  SEQ CHAPTER \h \r 1 ICF Consulting Review of Majersik, Steffans and
Caravati (2004)

Introduction 

ICF delivered a review of a preliminary conference abstract by Beck and
Caravati, “Neurotoxicity Associated with 1-Bromane Exposure” in
January 2003 (attached as an addendum).  The preliminary data reported
by Beck and Caravati were augmented by fuller descriptions of exposure
and medical information in a subsequent conference report by Majersik,
Steffans and Caravati 2004, “Chronic Exposure to 1- Bromopropane
Associated with Spastic Paraparesis and Distal Neuropathy: A Report of
Six Foam Gluers.”  In the Majersik et. al. report information
concerning medical follow up of the workers and exposure monitoring were
better described.  

Study Results 

As was reported by Beck and Caravati, the case report indicates that six
workers in a foam cushion factory were exposed to an adhesive mixture
containing 70% 1-BP, 0.3% 1,2-epoxybutane, 10% styrene-butadiene rubber,
and 20% rosin ester.  Three individuals were applying the glue with a
spray gun and the remaining three individuals were in close proximity to
the gluing station.  Majersik et. al. reports that these exposures were
measured by OSHA.  Three workers wore personal air sampling devices at
neck level and the air was sampled for their entire 8hr work day. The
"ventilation system" consisted of only passive fans.  The personal air
samplers were replaced twice for a total of 3x3=9 samples. No
information was given regarding the dimensions of the room.

Initially, OSHA told Caravati that the samples were taken after gluing
operations had been shut down and this is reflected in Beck and Caravati
and the documents written about the study in the summer of 2004.  In
fall 2004 Majersik spoke with OSHA officials again and was able to view
a video of the sampling procedure.  From the video Majersik determined
that the air samples were taken during gluing operations and not on the
day after gluing operations ceased. The OSHA inspector confirmed that he
took air samples during gluing operations, not the day after.  Dr.
Majersik confirmed that the gluers held the spray gun in their bare
hands and sprayed onto foam pads between waist and chest height so the
distance from the their breathing zone as at most a couple feet for the
active gluers (Personal Conversation on exposure with Dr. Majersik,
November 2004).  

In addition to the symptoms documented by Beck and Caravati below, all
patients complained of subacute onset of lower extremity pain or
paresthesias and 5 of 6 complained of difficulty walking.  After medical
exams, five patients had bilateral lower extremity spastic paraparesis,
distal sensory loss, and hyperreflexia. Serum bromide concentrations
ranged from 44 to 170 mg/dL (reference 0-40 mg/dL). Factitious
hyperchloremia was present with serum chloride concentrations of 105 to
139 mmol/L (reference 98-107 mmol/L). Air samples taken at the workplace
the day of gluing operations revealed a nPB mean air concentration of
130 ppm (range 91-176 ppm). As explained above, these levels are based
on personal monitors at nose level. Fifteen months later, the two most
severely affected patients had only regained minimal function and still
required assistance to walk; three patients continued to experience
chronic neuropathic pain. Chronic exposure to high vapor concentrations
of nPB in the workplace was associated with a distinct and
incapacitating neurotoxic syndrome.

Conclusion

The conclusions that ICF previously reported in the appended review
remain the same.  Had an AEL of 25ppm or lower been adhered to, these
medical effects would not have occurred.  

  



Addendum 

  SEQ CHAPTER \h \r 1 ICF Consulting Review of Beck and Caravati (2003)

ICF has been asked to review the conference abstract, “Neurotoxicity
Associated with 1-Bromane Exposure” by Beck and Caravati (2003). 
Further, ICF will discuss the relevance of this case report to other
studies in humans and will discuss whether this study allows for the
identification of an alternate NOAEL/LOAEL for the determination of an
Acceptable Exposure Limit for n-propylbromide (i.e., 1-bromopropane).

								

Study Results

The case report indicates that six workers in a foam cushion factory
were exposed to an adhesive mixture containing 70% 1-BP, 0.3%
1,2-epoxybutane, 10% styrene-butadiene rubber, and 20% rosin ester. 
Three individuals were applying the glue with a spray gun and the
remaining three individuals were in close proximity to the gluing
station.  The abstract did not indicate the distance of the six
individuals from the spray stream, but the working area was reportedly
poorly ventilated.  The mean air concentration of nPB was 130 ppm
(range, 91-176 ppm), but no details regarding the number of air samples
or their location were provided.  There were no other reported exposures
to potential neurotoxins, although exposure to other solvents in the
factory could not be ruled out based on the information reported in the
abstract.  The individuals tasked with spraying the glue reportedly did
not wear any latex gloves to protect their hands and it was not known
whether respirators were worn by exposed individuals in the factory. The
workers were exposed 30-40 hours/week for 3 months.

All six individuals complained of lower leg weakness, which increased
gradually in severity, pain, difficulty in standing and walking, and
numbness of the legs and feet.  Four workers (responsibilities not
specified) also exhibited hyperreflexia (increased reflex actions) and
hypertonicity (excessive tension of the muscles) of the lower
extremities.  Three individuals complained of occipital (back of the
head) headaches, while two workers complained of shortness of breath and
dizziness.  The serum bromide levels in the workers had a range of
44-170 mg/dL with concurrent serum chloride levels in the range of
105-139 mM.  After exposure was stopped, the workers' serum bromide
levels decreased (recovery levels were unreported) but the symptoms and
complaints remained for >2 months.

Conclusions

Because of the lack of specific information and the small number of
individuals studied, it is difficult to draw firm conclusions about the
human dose-response of potential nPB-induced toxicity in this case
report.  Nevertheless, the data indicate that all of the exposed
individuals exhibited peripheral neuropathy following three months'
exposure (6-8 hours/day) to a mean concentration of 130 ppm nPB in
combination with other solvents (epoxybutane, styrene, and butadiene). 
One-half of the individuals complained of headaches.  These data may
indicate that central nervous system effects lag behind those of the
peripheral nervous system, or require a larger cumulative dose of nPB. 
These data suggest that headaches are not a particularly sensitive
endpoint in humans exposed to nPB.  One significant limitation of the
presented data is the lack of specificity regarding which workers
complained of, or presented with, the reported symptoms.  Further, it is
not known how much nPB may have been absorbed through the skin following
dermal exposure to the sprayed glue; it can be inferred that dermal
exposure to the solvent contributed to the onset of symptoms.  Exposure
concentrations of the other compounds present in the glue formulation
were also missing from the case report and represent a significant gap
in the data.  Styrene is a central nervous system toxicant and there are
data indicating it also adversely impacts peripheral nerves
(IRIS-Styrene, 2003).  Butadiene has been identified as a reproductive
toxicant in mice, with potential reproductive toxicity in humans;
limited data exist regarding its neuroactive potential.

The possibility exists that the compounds may have acted synergistically
in the exposed individuals.  Certain epidemiological studies suggest a
syndrome known as psycho-organic syndrome, which has been used to
describe the symptomatology observed in workers heavily exposed to a
variety of organic solvents (IRIS-Styrene, 2003).  Examples of specific
effects include neurasthenia (nervous exhaustion and functional
fatigue), personality alterations, unsteadiness, dizziness, and vertigo,
some of which were complaints of the exposed individuals in this case
report. 

Even with these limitations, however, the data indicate that significant
and persistent peripheral neurotoxicity occurs following subchronic
exposure to a minimum of 91 ppm nPB in the air.  These data indicate
that an AEL of 25 ppm or lower is prudent and protective of human health
for occupational workers and that an AEL of 60-90 ppm is not
recommended.  Further, the data indicate that gloves should be worn by
all personnel working with sprayed adhesives containing nPB.  The
effects in this case report are consistent with those reported in other
case studies (Ichihara et al., 2002; Sclar, 1999).  This case report
does not provide data useful for the identification of a NOAEL or LOAEL
for nPB.

References

Beck BR, and Caravati EM.  2003. Neurotoxicity associated with
1-bromopropane exposure.  Abstract 210. J Toxicology Clinical Toxicology
 41(5):729 August 2003.

Ichihara, G. et al. 2002.  Neurological disorders in three workers
exposed to 1-bromopropane.  J Occup Health 44:1-7.

IRIS-Styrene. 2003.  Integrated Risk Information System. Profile for
styrene.  Downloaded November, 2003.

Majersik, Steffans and Caravati “Chronic Exposure to 1-Bromopropane
Associated with Spastic Paraparesis and Distal Neuropathy: A Report of
Six Foam Cushion Gluers” Salt Lake City, Utah.  A study presented
October 5, 2004, at the 129th annual meeting of the American
Neurological Association in Toronto. 

Majersik, Jennifer (2002) E-mail from Dr. Jennifer Majersik to ICF
Consulting, containing information on exposure scenario in the report
“Chronic Exposure to 1-Bromopropane Associated with Spastic
Paraparesis and Distal Neuropathy: A Report of Six Foam Cushion
Gluers,” November 2004

Sclar G. 1999.  Encephalomyeloradiculoneuropathy following exposure to
an industrial solvent. Clin Neurol Neurosurg 101(3):199-202.

***DRAFT – December 13, 2004 – DO NOT CITE OR QUOTE***

