http://www.findarticles.com/cf_dls/m0907/1_58/101860467/print.jhtml

Toxic effects of chemical mixtures.

Archives of Environmental Health, Jan, 2003, by Harold I. Zeliger

ABSTRACT. Exposures to chemical mixtures have reportedly produced
unexpected effects. Examination of new case studies, as well as those
previously reported, shows that when the human body is exposed to
mixtures of chemicals that include lipophilic and hydrophilic species,
the lipophiles facilitate the absorption of the hydrophiles at enhanced
levels and produce effects that are not expected from an individual
chemical. These effects include enhanced acute and chronic responses,
low-level concentration response, and unexpected target organ attack.
Octanol:water partition coefficients are predictive of relative
lipophilicity and hydrophilicity. The findings have implications for
safe drinking water standards, air quality standards, safe industrial
and environmental exposure levels, product formulation, product
labeling, and protocols for toxicity testing of chemical products.

<Key words: additive effects, Aerospace Syndrome, chemical mixtures,
hydrophilic chemicals, lipophilic chemicals, low-level exposure,
octanol:water partition coefficient, potentiation, synergistic effects,
Sick Building Syndrome, toxic chemicals, toxicity of chemical mixtures>

**********

A REVIEW OF THE TOXICOLOGICAL LITERATURE reveals that exposure to
chemicals can produce unexpected effects. (1,2) Some chemical exposures
have resulted in unpredicted target organ attack (3,4); others have
shown effects much greater than anticipated from the known etiology.
(5-7) Many researchers have been baffled by the unexpected effects
observed following exposure of individuals to low levels of chemical
toxins. (8-10) This investigator also has noted such effects, and for a
long time was unable to understand or explain them. A study of published
and observed effects, however, has revealed that all of these unusual
effects have a common thread: The exposures have always occurred in
response to mixtures of chemicals--not to individual compounds.

Many published studies describe the combined effects of exposure to
chemical mixtures. These effects can be additive, antagonistic,
synergistic, or potentiated. (1,6,11-14) Most of the studies address
relatively high exposure levels--either at or exceeding established
threshold limit values (TLVs). The few studies that report unusual
effects from exposure to low-level chemical mixtures concede that
unknown factors may contribute to the observed effects. (8,10,15)

All of the cases cited in the literature, and those reported for the
first time here, describe unusual and unpredicted effects, and the
chemical mixtures that produced such effects contained at least 1
relatively lipophilic chemical and 1 relatively hydrophilic chemical.
The relative differences in lipophilicity and hydrophilicity are
reflected by the octanol:water partition coefficients of the chemicals,
[K.sub.ow]. (16)

[K.sub.ow] is indicative of the relative lipophilic character of a given
chemical. It is defined as the ratio of that quantity of chemical
dissolved in the octanol phase to that dissolved in the water phase of
an octanol-water mixture. It is expressed as a logarithm of the number
because there exists a wide range in [K.sub.ow] for different compounds.
The values have no units. The [K.sub.ow] data reported herein range from
less than -1.0 to more than 6.0. Higher values indicate more lipophilic
character, and lower values indicate more hydrophilic character.

Mucous membranes coat most body tissues and serve as the body's primary
barrier to absorption of chemicals. (17) It is well established that
lipophilic chemicals can penetrate mucous membranes much more readily
than can hydrophilic chemicals, (1) and mucous membrane barriers thus
protect the body from absorbing hydrophilic chemicals. (18) Lipophilic
chemicals can promote the permeation of hydrophilic chemicals, and are
routinely employed in drug delivery systems. (19-21) Manganaro noted
that most drugs do not penetrate epithelial barriers at rates sufficient
for clinical usefulness without the use of permeability enhancers. (20)
He quantitatively related the effects of permeabilizers on the in vitro
penetration of propanolol through porcine buccal epithelium. (21)

The relationship between mucous membrane permeability and [K.sub.ow] can
be seen from the literature. Kitagawa and Sato (19) reported that
permeability coefficients across excised guinea pig dorsal skin
increased directly with increased [K.sub.ow] for a homologous series of
parabens. Potts and Guy (22) noted that skin permeability is a function
of [K.sub.ow]. Boman and Maibach (23) determined that the percutaneous
absorption of hydrophile butanol (low [K.sub.ow]) increased by
simultaneous exposure to an ionic surfactant lipophile (higher
[K.sub.ow]). Siegel (24,25) reported that an increase in lipid
solubility produced an increased permeability in the oral mucosa of New
Zealand rabbits and rats. Siegel's permeation constants correlate
exactly with [K.sub.ow] values. Geyer et al. (26) reported a
quantitative correlation between [K.sub.ow] and the bioaccumulation
potential of organic chemicals by green alga. Scheuplein and Ross (27)
reported that skin permeability was increased after treatment with
nonpolar solvents, and that permeability constants for a homologous
series of alcohols were a function of carbon number. This relationship
corresponds exactly to increasing [K.sub.ow] values. Witte et al. (18)
determined that subtoxic concentrations of membrane-damaging compounds
enhanced the cytotoxicity of hydrophilic xenobiotics. Witte postulated
that combinations of lipophilic and hydrophilic compounds would show
synergistic effects resulting from membrane damage by lipophilic species
and increased uptake of hydrophilic species. The data reported
demonstrated a linear relationship between the logarithm of the
no-observed-effect concentration (NOEC) and the [K.sub.ow] value. The
higher the [K.sub.ow], the lower the log NOEC, and the greater the
toxicity of the mixture.

It is proposed herein that the heretofore unexpected effects of exposure
to mixtures of chemicals should be expected when at least 1 is a
lipophile (higher [K.sub.ow]) that facilitates the absorption of at
least 1 hydrophile (lower [K.sub.ow]) in the mixture. As a result of the
facilitated absorption, chemicals that alone would be innocuous are
absorbed at levels that produce toxic effects. Hence, one observes
enhanced effects of exposure to such chemical mixtures at relatively
high concentrations, and at low levels of exposure effects are absent!
It is also proposed that the combination of lipophile and hydrophile can
target organs not attacked by the individual chemicals, and such
combinations can produce effects that are not anticipated from the known
toxicology of the individual chemicals.

Materials and Method

This is an empirical study based on an analysis of 23 case studies, 20
of which have been reported previously in the literature. Medical
evaluations and industrial hygiene data for the previously published
cases were accepted as published. For the 3 case studies reported herein
for the 1st time, the human health effects noted were diagnosed by
appropriate clinical examinations, and industrial hygiene data were
generated in accordance with accepted protocols.

Experimental [K.sub.ow] values for compounds were used when available;
otherwise, calculated values were used. (16) All calculated values are
identified with an asterisk.

Herein, low-level exposures represent exposures to concentrations below
the published TLV, permissible exposure level (PEL), or maximum
contamination level (MCL); and high-level exposures are those that
exceed the TLV, PEL, or MCL.

Results

The following studies of groups of individuals are representative of the
exposure effects noted. In all instances, the [K.sub.ow] values are
given in brackets that follow the chemical name.

Group 1. Burkhart et al. (28) described a 39-member group that reported
respiratory symptoms within hours of exposure to a reformulated aerosol
spray leather protector. (28) The reformulated product contained
isobutane [2.76], ethyl acetate [0.73], n-heptane [4.66], and
fluoroaliphatics [0.75]. Most patients reported symptoms immediately, or
within minutes of application. Some of those exposed had used the
product outdoors where ventilation was good. Clearly, the clinical
response of many, if not most, of those exposed cannot be explained by
the published data for the individual chemicals. Similar results have
been reported by Van Essen. (29)

Group 2. Cone and Sult (30) reported a "mystery illness" that affected
17 workers who complained of central nervous system (CNS) and
respiratory symptoms following fumigation of a casino with a mixture of
carbamate propoxur [1.52], coumaphos [4.13], 1,1,1-trichloroethane
[2.49], methylene chloride [1.25], xylene [3.15], and acetone [-0.24].
Industrial hygiene evaluation revealed only trace quantities of the
chemicals noted, yet pesticide poisoning symptoms were observed.

Group 3. Dossing and Ranek (15) reported on 3 previously healthy workers
who were hospitalized with liver injury following 2-4 mo of exposure to
a mixture of carbon disulfide [1.94], toluene [2.73], methanol [-0.77],
and trace quantities of other organic compounds. Concentrations of all
species were below PELs, and hepatotoxicity was not predicted. The
authors suggested that "liver injury was caused by the combined action
of organic solvents." A synergistic and hepatotoxic reaction was
suspected.

Groups 4 and 5. Mutti et al. (31) described CNS effects that resulted
from exposure of shoemakers to n-hexane [3.90], cyclohexane [3.44],
methylethyl ketone (MEK) [0.29], and ethyl acetate [0.73]. All 4
chemicals were present in concentrations below TLVs when measured in the
workers' breathing zones. Valentini et al. (32) reported peripheral
neurotoxicity following exposure of a shoemaker to MEK [0.29], ethyl
acetate [0.73], cyclohexane [3.44], n-heptane [4.66], and isomers of
hexane and cyclohexane. All exposures were below the TLV. The authors
hypothesized that MEK might have potentiated the neurotoxicity of
n-heptane, just as it does for n-hexane. Both of these studies
demonstrated the onset of neurotoxic effects from exposures to low-level
chemical concentrations.

Group 6. In a case studied by this investigator, low levels of an
applied herbicide/pesticide mix were drawn into the uptake air of a
commercial building. Several individuals immediately reported CNS and
respiratory symptoms, and 1 sustained permanent respiratory injury. The
chemical mix contained (2,4-dichlorophenoxy) acetic acid (2,4-D) [0.65],
2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP) [3.13],
3,6-dichloro-o-anisic acid (Dicamba) [1.13], solvent naphtha with 14%
naphthalene [3.30], and dinitroaniline [1.29]--all of which were at
concentrations far below the TLV.

Group 7. Horowitz et al. (33) reported peripheral nervous system chronic
effects in farmers who applied pesticide solutions. Many of the
solutions used were xylene [3.15] solutions of methyl parathion [2.86],
tetraethylpyrophosphate [0.45], and azinphos-methyl [2.75] pesticides.
The levels of exposure for each of these chemicals were below those that
would induce acute or subacute symptomology. Here, too, it is believed
that the xylene solvent facilitated the absorption of
greater-than-expected quantities of the pesticides. Blain (34) described
central and peripheral nervous system effects associated with low-level
exposures to organophosphates. Blain did not identify specific
pesticides or solvents, but one can safely assume that given the
pesticides were organophosphates, they were dissolved in solvents with
relatively high [K.sub.ow] values.

Group 8. Kilburn et al. (4) reported respiratory and neurobehavioral
symptoms, as well as disturbed mental or neurologic function, in
histology technicians as a result of their exposure to formaldehyde
[0.35], chloroform [1.97], toluene [2.73], xylene [3.15], and ethanol
[-0.31]. Kilburn's study was the 1st report of such neurological
symptoms that could be attributed to these chemicals.

Group 9. Lee et al. (8) described pulmonary and upper respiratory tract
symptoms among newspaper pressmen exposed to solvents. He attributed the
prevalence of symptoms to a combination of solvent and lubricant
exposure, even though exposures were below PELs. The chemicals included
aliphatic hydrocarbons, glycol ethers, isopropanol, limonene, naphtha,
oils, and varnishes. These chemicals have [K.sub.ow] values ranging from
0.05 to 4.57.

Group 10. In 1980, 21 workers at a large printing ink company reported
eye and skin irritation, headache, dyspnea, and nausea symptoms that
occurred while they were at work. The National Institute for
Occupational Safety and Health (35) investigated and found methanol
[0.77], ethanol [-0.31], isopropanol [0.05], MEK [0.29], methylisobutyl
ketone [1.19], ethyl acetate [0.73], n-propyl acetate [1.24], toluene
[2.73], xylene [3.15], and benzophenone [3.18]. All were measured at
concentrations well below the recommended PELs.

Group 11. White et al. (36) reported acute and chronic CNS effects among
workers in the screen-printing industry. Investigation revealed that
these workers were exposed to toluene [2.73], MEK [0.29], mineral
spirits (a mixture of compounds with [K.sub.ow] in the 3.0-4.0 range),
methylene chloride [1.25], and acetic acid [-0.17]. All exposures were
at concentrations below TLVs.

Group 12. In 1988, more than half of approximately 200 employees working
with composite plastic materials in 1 building of a large aircraft
manufacturing company reported CNS, respiratory, heart, and
gastrointestinal symptoms. Sparks et al. (37) investigated what was
dubbed the "Aerospace Syndrome" and found the presence of phenol [1.46],
formaldehyde [0.35], styrene [2.95], methylene chloride (1.25), methanol
(-0.77), C9-C12 alkanes, and aromatics ([K.sub.ow] values 3.0-4.0),
particulates, and epoxy resin. All exposures were at levels well below
PEL. Sparks concluded that that "psychosocial factors in the workplace
and community are likely to have been major contributors to this
outbreak of illness."

Group 13. Koren et al. (38) studied "Sick Building Syndrome"--a set of
symptoms associated with the air quality typically found in new homes
and offices. Symptoms included eye, nose, and throat irritation;
headache; mental fatigue; and respiratory distress. Fourteen people were
exposed to a mixture of volatile organic chemicals characteristic of
those found in new homes and offices. All chemicals were at
concentrations far below levels considered hazardous. The 22 chemicals
included aliphatic and aromatic hydrocarbons, aldehydes, ketones,
alcohols, and esters. [K.sub.ow] values ranged from 0.05 to 5.74.
Respiratory responses were noted immediately upon exposure, 4 hr later,
and 18 hr later. Individual concentrations or additive effects could not
account for the respiratory response.

Individual 14. In a case examined by the instant author, a 56-yr-old
purchaser of a new yacht reported the onset of dyspnea, a tight chest,
and coughing whenever she was in the closed cabin. Within 3 mo she
developed permanent asthmatic symptoms. Ambient air measurements in the
cabin showed the presence of formaldehyde [0.35], toluene [2.73], and
benzene [2.13]--all at concentrations below those believed to produce
respiratory effects.

Group 15. Gamble et al. (5) described respiratory effects on rubber
workers exposed to resorcinol [0.80], formaldehyde [0.35], ammonia
[-1.38], and particulates at levels far below the TLV. The exposures
affected several organs. Acute decreases in lung function over a shift,
difficulty breathing, itch, rash, chest tightness, burning eyes,
persistent cough, and phlegm were noted. Gamble suggested that
"formaldehyde carriers" carry formaldehyde deep into the lung, where it
has a greater toxic effect.

Group 16. Harving et al. (39) tested volunteer subjects who were exposed
to formaldehyde concentrations as high as 2.0 mg/[m.sup.3], which
exceeded the PEL of 1.2 mg/[m.sup.3], and these levels did not cause
lower-airway problems. No other chemicals were present in these
individuals.

Group 17. Liu et al. (40) reported that occupational studies revealed
that bronchial asthma resulted from exposure to formaldehyde at
concentrations of less than 1.0 ppm. (Occupational exposures to
formaldehyde are almost always accompanied by exposure to other
chemicals.) However, these results, were not repeated in chamber tests
with no other chemicals present.


Group 18. Alexandersson and Kolmondin-Hedman (3) reported on
formaldehyde exposure in woodworkers. Very low levels of formaldehyde
[0.35] produced dyspnea and other lower-lung symptoms; however, low
levels of terpenes [4.57-4.83] were also present, as were dusts.

Individual 19. A carpet exposure case was examined by this investigator.
Shortly after the installation of new carpeting in a home, a 40-yr-old
woman experienced respiratory, CNS, and allergic symptoms. Her condition
worsened until the carpet was removed. Sampling of the ambient air in
the home revealed more than 80 different chemicals. These included
formaldehyde [0.35], several other aldehydes, ketones, aliphatic and
aromatic hydrocarbons, glycol ethers, organic acids, and alcohols. The
concentrations of all species were well within levels considered safe
for human exposure. The [K.sub.ow] values for the chemicals ranged from
-0.31 to 5.74.

Groups 20 and 21 and individual 22. Brooks et al. (7) reported the onset
of Reactive Airways Dysfunction Syndrome (RADS) in painters who applied
vinyl latex primer in 1 instance and an oil-base enamel in another
instance. The specific paints were not identified; however, a review of
paint formulations shows that each had components that were relatively
lipophilic and relatively hydrophilic. Brooks (7) also described an
individual who developed RADS after applying a floor sealant that
contained decane [5.01], ethylbenzene [3.15], toluene [2.73], xylene
[3.15], and epichlorhydrin [0.45]. Although industrial hygiene
evaluations were not performed in these 3 instances, it can be inferred
that the exposure concentrations were relatively high because all
individuals were working in enclosed environments.

Mice (group 23). Porter et al. (41) found that, although there was
little or no observed biological effect of nitrates [-4.39] alone--or of
the pesticides Aldicarb [1.13] and Atrazine [2.61] alone--when they were
consumed in drinking water at the MCLs for groundwater, the combination
of pesticide and nitrate altered immune, endocrine, and nervous system
parameters in mice.

Discussion

In each of the cases reported earlier, at least 1 relatively lipophilic
(higher [K.sub.ow]) chemical and 1 relatively hydrophilic (lower
[K.sub.ow]) chemical were present. The leather-treatment exposures
described by Burkhart et al. (28) and Van Essen (29) are typical of
hundreds of similar cases that were reported nationwide in the 1990s.

The pesticide exposure cases discussed by Cone and Sult, (30) Horowitz
et al., (33) and the current investigator (group 6 herein) are exemplars
of numerous reports of pesticide poisonings at low levels of exposure.

The hepatotoxic effects noted by Dossing and Ranek (15) are similar to
those reported by Sontaniemi et al. (42) concerning painters and
chemical industry workers who were exposed to low levels of chemicals
(i.e., levels that did not exceed authorized concentrations). Sontaniemi
(42) discussed mixtures of 20+ chemicals, including alcohols and ketones
(low [K.sub.ow] values); esters, glycol ethers, and chlorinated
hydrocarbons (intermediate [K.sub.ow] values); and aliphatic and
aromatic hydrocarbons (high [K.sub.ow] values).

The neurological effects on shoemakers reported by Mutti et al. (31) and
Valentini et al. (32) corresponded with the known potentiation of the
effects of MEK with hexane. (14) What was of interest, however, was the
presence of such an effect with low levels of exposure.

The description by Kilburn et al. (4) of neurobehavioral symptoms and
disturbed mental function is of interest because it demonstrated effects
from the mixture of chemicals that are not associated with the
individual chemical species present. This is indicative of the
unexpected effects that may result from exposure to mixtures of
relatively lipophilic and relatively hydrophilic chemicals.

The work of Lee et al., (8) the National Institute of Occupational
Safety and Health, (35) and White et al. (36) demonstrated the acute and
chronic effects of printing industry solvents on those exposed to levels
below the TLV. In all 3 cases, the mixtures contained relatively
lipophilic and hydrophilic species. This investigator has examined
several other printing industry exposure cases that produced similar CNS
and respiratory symptoms.

The work of Sparks et al. (37) on "Aerospace Syndrome" is indicative of
many industrial hygiene studies that do not provide evidence of a
connection between exposure levels of individual chemical species and
symptoms. What the authors did not consider were the combined effects of
the various chemicals. Several relatively hydrophilic species (e.g.,
formaldehyde, methanol, methylene chloride), as well as numerous
relatively lipophilic species (e.g., styrene, aliphatic and aromatic
hydrocarbons) were present. Again, one observes effects of the mixture
that are not associated with low-level concentrations of the individual
chemical species.

The study by Koren et al. (38) of "Sick Building Syndrome" was
interesting because it was indicative of many similar studies that have
involved both the workplace and the home. The chemicals found included
many that were relatively lipophilic, as well as many that were
relatively hydrophilic. Combined, they produced CNS and respiratory
effects. The symptoms reported in the current study are similar to those
described in several other studies involving low-level exposures to
mixtures of such chemicals from new carpeting. (43-46) As exemplified by
Dietert and Hedge, (43) many of these studies have concluded that the
concentration levels of the individual components are insufficient to
produce toxic effects. The results reported earlier in group 19 suggest
otherwise. As was the case in the "Aerospace Syndrome" study, sick
building and new carpet exposure effects are often considered
psychological and attributable to a sensory stimulus, such as odor. (9)

Formaldehyde is a widely used industrial chemical that enters the home
environment as a component of insulation, carpeting, plywood, and
particleboard. It is an upper respiratory irritant and a carcinogen.
(47) Not surprisingly, therefore, it has been the subject of much
scrutiny. Seven of the group studies described herein involved symptoms
that resulted from exposure to formaldehyde. Five of these--groups 8,
14, 15, 18, and 19--were exposed to low-level exposure. In all these
reports, exposures to formaldehyde were accompanied by simultaneous
exposure to at least 1 other chemical that was more lipophilic than
formaldehyde, and these exposures produced lower-airway symptoms. Gamble
et al. (5) suggested that "formaldehyde carriers" carry the chemical
deep into the lung, where it has greater effect. The study by Harving et
al. (39) is significant in this regard. The researchers found that, when
formaldehyde was tested alone, even exposures higher than TLV did not
result in lower-airway problems for the volunteer subjects. The findings
of Liu et al. (40) are consistent with this. They reported that
occupational exposures to formaldehyde at concentrations below the TLV,
when other chemicals were present, resulted in bronchial asthma, but
that such results were not repeated in chamber tests where no other
chemicals were present. The authors stated that occupational exposures
to formaldehyde were almost always accompanied by exposure to other
chemicals as well.

Brooks et al., in their classic paper, described the onset of Reactive
Airways Dysfunction Syndrome. (7) Of the 10 cases cited, 7 involved
chemical mixtures. Several of the cases involved paints and coatings
whose chemical components, individually, are not known to induce RADS
symptoms. A review of the chemical compositions of the products involved
revealed that, in all 7 cases, exposures were to mixtures of relatively
lipophilic and relatively hydrophilic chemicals.

The Porter et al. study (41) is the only one in which human exposure was
not addressed. It is significant, however, because it demonstrated how
wide-ranging the unexpected effects of exposure to even minute
quantities of chemical mixtures of lipophiles and hydrophiles can be. It
also serves as a warning on the dangers of drinking contaminated water.

Research by Witte et al. (18) established conclusively that lipophilic
compounds enhance the toxicity of hydrophilic chemicals that, in
themselves, have a low capacity to penetrate cell membranes (a low
[K.sub.ow]), and that this enhancement effect increases with increased
[K.sub.ow] values of the lipophiles. Although Porter et al. (41) did not
mention [K.sub.ow] values, the research reported demonstrated the
presence of unexpected effects resulting from exposures to mixtures of
lipophiles and hydrophiles at very low concentrations (i.e., those
permitted in drinking water). The studies presented above support these
concepts in human exposure.

Conclusions

The present review of group studies demonstrated that exposures to
chemical mixtures of differing lipophilicity may produce
greater-than-anticipated effects--that is, more severe symptoms,
unpredicted effects on organs not known to be affected by the individual
components, and effects at concentrations much lower than those known to
be harmful for the individual components. Therefore, concentrations of
individual chemicals in a mixture to which one is exposed are not
necessarily indicative of the ultimate effects. The quantities absorbed
are of greater significance.

It is postulated that, in all exposures to mixtures of chemicals with
varying [K.sub.ow] values, a lipophilic species promotes permeation of a
hydrophilic species through a mucous membrane. This results in the
absorption of greater quantities of hydrophilic species than would be
absorbed if the lipophile were not present. The enhanced effects likely
result from this greater absorption. Absorption may occur through the
skin, by ingestion, or via inhalation. No mechanism for the action, once
absorbed, is offered. However, once absorbed, the mixtures of chemicals
may affect the body in ways not anticipated from the actions of single
chemicals alone. The effects of the absorbed mixtures may be acute or
chronic. The time from absorption until the onset of symptoms, the
target organ(s), and the severity of the effect(s) cannot be predicted
at this time.

These findings have several important implications. They show that
exposure to chemical mixtures of differing [K.sub.ow] likely produce
reactions that may not be associated with the individual chemicals.
Persons who present with "strange" symptoms following exposure to
chemical mixtures should not be assumed to have been exposed
benignly--examples include individuals who present with symptoms
following installation of new carpeting, or after use of a spray-applied
pesticide product, or following exposure to a combination of solvents,
mold, and mildew. What is important is that the effects be connected to
the exposures, even if the symptoms do not correspond to the known
effects of the individual chemicals.



The concentrations of the individual chemicals in a mixture to which one
is exposed are not necessarily indicative of the ultimate effects. The
quantities absorbed are of greater significance, and the amounts
absorbed may be related to increased permeation of a relatively
hydrophilic species aided by a relatively lipophilic species.

All low-level exposures to toxic chemicals that produced unanticipated
effects were exposures to mixtures of chemicals that contained at least
1 relatively lipophilic and 1 relatively hydrophilic species. The
reported group studies included both acute and chronic responses.
Reactions to high-level concentrations are postulated to be
greater--with more severe symptoms--due to the absorption of increased
quantities of the chemicals.

The findings reported herein suggest that the TLV and PEL values for
individual chemical species do not necessarily apply to mixtures.
Accordingly, standards for drinking water and air quality may require
revision, thus reflecting effects of chemical mixtures. The effects of
exposures to chemicals, as well as to the actions of pharmaceutical
products, may also require scrutiny, and some chemical products may
require reformulation to produce safer products. The potential combined
effects of simultaneous exposure to toxic chemicals and ingestion of
food should also be addressed. Toxicities should be determined for
mixtures, rather than for individual chemical species. Research in these
areas is ongoing.

Submitted for publication June 14, 2002; revised; accepted for
publication October 30, 2002.

Requests for reprints should be sent to Dr. Harold I. Zeliger, Zeliger
Chemical, Environmental & Toxicological Services, 1270 Sacandaga Road,
West Charlton, NY 12010.

E-mail: hiz@...

References

(1.) Alessio L. Multiple exposure to solvents in the workplace. Int Arch
Occup Environ Health 1996; 69:1-4.

(2.) Feron VJ, Groten JP, Jonker D, et al. Toxicology of chemical
mixtures. Toxicology 1995; 105:415-27.

(3.) Alexandersson R, Kolmodin-Hedman B. Exposure to formaldehyde:
effects on pulmonary function. Arch Environ Health 1982; 37(5):279-84.

(4.) Kilburn KH, Seidman BC, Warshaw R. Neurobehavioral and respiratory
symptoms of formaldehyde and xylene exposure in histology technicians.
Arch Environ Health 1985; 40(4):229-33.

(5.) Gamble JF, McMichael AJ, Williams T, et al. Respiratory function
and symptoms: an environmental-epidemiological study of rubber workers
exposed to a phenol-formaldehyde type resin. Am Ind Hyg Assoc J 1976;
37:499-513.

(6.) Haghdoost NR, Newman LM, Johnson EM. Multiple chemical exposures:
synergist vs. individual exposure levels. Reprod Toxicol 1997;
11(1):9-27.

(7.) Brooks SM, Weiss MA, Bernstein IL. Reactive Airways Dysfunction
Syndrome (RADS): persistent asthma syndrome after high level exposures.
Chest 1985; 88(3):376-84.

(8.) Lee BW, Kelsey KT, Hashimoto D, et al. The prevalence of pulmonary
and upper respiratory tract symptoms and spirometric test findings among
newspaper pressroom workers exposed to solvents. J Occup Environ Med
1997; 39(10):960-69.



(9.) Lynch RM, Kipen H. Building-related illnesses and employee lost
time following application of hot asphalt roof: a call for prevention.
Toxicol Ind Health 1998; 14(6):857-68.

(10.) Hansen MK, Larsen M, Cohr KH. Waterborne paints: a review of their
chemistry and toxicology and the results of determinations made during
their use. Scand J Work Environ Health 1987; 13: 473-85.

(11.) Tse SYH, Mak T, Weglicki WB, et al. Chlorinated aliphatic
hydrocarbons promote lipid peroxidation in vascular cells. J Toxicol
Environ Health 1990; 31:217-26.

(12.) Mahdiy SAB, Knowles CO. Phthalate-organophosphate interactions:
toxicity, penetration, and metabolism studies with house flies. Arch
Environ Contam Toxicol 1980; 9:147-61.

(13.) Stratton GW. The influence of solvent type on solvent-pesticide
interactions in bioassays. Arch Environ Contam Toxicol 1985; 14: 651-58.

(14.) Takeuki Y, Ono Y, Hisanaga N, et al. An experimental study of the
combined effects of n-hexane and methyl ethyl ketone. Br J Ind Med 1983;
40:199-203.

(15.) Dossing M, Ranek L. Isolated liver damage in chemical workers. Br
J Ind Med 1984; 41:142-44.

(16.) Syracuse Research Corporation. Interactive LogKow. Available from:
http://esc.syrres.com/interkow/kowdemo.htm

(17.) Rea WJ. Chemical Sensitivity, Vol 1. Boca Raton, FL: Lewis
Publishers, 1992; pp 52-53.

(18.) Witte I, Jacobi H, Juhl-Strauss U. Correlation of synergistic
cytotoxic effects of environmental chemicals in human fibroblasts with
their lipophilicity. Chemosphere 1995; 31(9):4041-49.

(19.) Kitagawa S, Li H, Sato S. Skin permeation of parabens in excised
guinea pig dorsal skin, its modification by penetration enhancers and
their relationship with n-octanol/water partition coefficients. Chem
Pharm Bull (Tokyo) 1997; 45(8):1354-57.

(20.) Manganaro AM. Review of transmucosal drug delivery. Mil Med 1997;
162:27-30.

(21.) Manganaro AM, Wertz PW. The effects of permeabilizers on the in
vitro penetration of propanolol through porcine buccal epithelium. Mil
Med 1996; 161:669-72.

(22.) Potts RO, Guy RH. Predicting skin permeability. Pharm Res 1992;
9(5):663-69.

(23.) Boman A, Maibach HI. Percutaneous absorption of organic solvents.
Int J Occup Environ Health 2000; 6:93-95.

(24.) Siegel IA. Effect of chemical structure on nonelectrolyte
penetration of oral mucosa. J Invest Dermatol 1981; 76:137-40.

(25.) Siegel IA. Permeability of the rat oral mucosa to organic solutes
measured in vivo. Arch Oral Biol 1984; 29:13-16.

(26.) Geyer H, Politzki G, Freitag D. Prediction of ecotoxicological
behaviour of chemicals: relationship between n-octanol/water partition
coefficient and bioaccumulation of organic chemicals by alga chlorella.
Chemosphere 1984; 13(2):269-84.

(27.) Scheuplein RJ, Ross L. Effects of surfactants and solvents on the
permeability of epidermis. J Soc Cosmetol Chem 1970; 21:853-73.

(28.) Burkhart KK, Britt A, Petrini G, et al. Pulmonary toxicity
following exposure to an aerosolized leather protector. Clin Toxicol
1996; 34(1):21-24.


(29.) Von Essen S. Reformulated leather protectors: safer for the ozone
than the public. Clin Toxicol 1996; 34(1):25-26.

(30.) Cone JE, Sult TA. Acquired Intolerance to Solvents Following Acute
Pesticide/Solvent Intoxication in a Building. Washington, DC: U.S.
Department of Labor, Occupational Safety and Health Administration,
1991. Report No. 0030-CONE-91-012.

(31.) Mutti A, Cavatorta A, Lommi G, et al. Neurophysiological effects
of long-term exposure to hydrocarbon mixtures. Arch Toxicol 1982; Suppl
5:120-24.

(32.) Valentini F, Agnesi R, Dal Vecchio L, et al. Does n-heptane cause
peripheral neurotoxicity? A case report in a shoemaker. Occup Med 1994;
44:102-04.

(33.) Horowitz SH, Stark A, Marshall E, et al. A multi-modality
assessment of peripheral nerve function in organophosphate-pesticide
applicators. J Occup Environ Med 1999; 41(5):405-08.

(34.) Blain PG. Adverse health effects after low level exposure to
organophosphates. Occup Environ Med 2001; 58:689-90.

(35.) Stephenson RL, Jannerfeldt E. Health Hazard Evaluation:
Consolidated Printing Ink Company, St. Paul, MN. Cincinnati, OH: U.S.
National Institute for Occupational Safety and Health, 1981. Report No.
HHE-80-046-914.

(36.) White RF, Proctor SP, Echeverria D, et al. Neurobehavioral effects
of acute and chronic mixed-solvent exposure in the screen printing
industry. Am J Ind Med 1995; 28:221-31.

(37.) Sparks PJ, Simon GE, Katon WJ, et al. An outbreak of illness among
aerospace workers. West J Med 1990; 153(1):28-33.

(38.) Koren HS, Graham DE, Devlin RB. Exposure of humans to a volatile
organic mixture. III. Inflammatory response. Arch Environ Health 1992;
47(1):39-44.

(39.) Harving H, Korsgaard J, Dahl R, et al. Low concentrations of
formaldehyde in bronchial asthma: a study of exposure under controlled
conditions. Br Med J 1986; 293:310.

(40.) Liu KS, Huang FY, Hayward SB, et al. Irritant effects of
formaldehyde exposure in mobile homes. Environ Health Perspect 1991;
94:91-94.

(41.) Porter WP, Jaeger JW, Carlson IH. Endocrine, immune, and
behavioral effects of aldicarb (carbamate), atrazine (triazine) and
nitrate (fertilizer) mixtures at groundwater concentrations. Toxicol Ind
Health 1999; 15(1-2):133-50.

(42.) Sontaniemi EA, Sutinen S, Sutinen S, et al. Liver injury in
subjects occupationally exposed to chemicals in low doses. Acta Med
Scand 1982; 212:207-15.

(43.) Dietert RR, Hedge A. Toxicological considerations in evaluating
indoor air quality and human health: impact of new carpet emissions.
Crit Rev Toxicol 1996; 26(6):633-707.

(44.) Hodgson AT, Wooley JD, Daisey JM. Volatile Organic Chemical
Emissions from Carpets. Final Report. Bethesda, MD: U.S. Consumer
Product Safety Commission, Directorate for Health Services, 1992. Report
No. CPSC-IAG-90-1256.

(45.) Stadler JC, Kennedy, GL Jr. Evaluation of the sensory irritation
potential of volatile organic chemicals from carpets--alone or in
combination. Food Chem Toxicol 1996; 34:1125-30.

(46.) Tepper JS, Moser VC, Costa DL, et al. Toxicological and chemical
evaluation of emissions from carpet samples. Am Ind Hyg Assoc J 1995;
56:158-70.

(47.) Sax NI, Lewis RJ Sr. Dangerous Properties of Industrial Materials.
7th ed. New York: Van Nostrand Reinhold, 1991; pp 1764-65.


HAROLD I. ZELIGER
Zeliger Chemical, Environmental
& Toxicological Services
West Charlton, New York



COPYRIGHT 2003 Heldref Publications in association with The Gale Group
and LookSmart. COPYRIGHT 2003 Gale Group


--
This is message #186.
**********

To post, send mail to <gwvm@...>.
To unsubscribe, send mail to <gwvm-unsubscribe@...>.
(This may fail if your address has changed since you signed
up; if so, or for other assistance, contact
<gwvm-owner@...>.)

This list is hosted by Online Policy Group, Inc. For more information
about our work on Internet access, the digital divide, and preventing
online discrimination, see <http://www.onlinepolicy.org>.
You may request free email, mailing list, and web services at
<http://www.onlinepolicy.org/services.shtml>.
Donations accepted at <http://onlinepolicy.org/joindonate.shtml>.