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Isopropyl Alcohol and aggravation of liver disease?

Chuck Miller rellim at MAILHOST.TCS.TULANE.EDU
Mon Nov 2 11:42:54 EST 1998

Here are a few references to get you started.

Regul Toxicol Pharmacol 1996 Jun;23(3):183-92

Isopropanol: summary of TSCA test rule studies and relevance to hazard

Kapp RW Jr, Bevan C, Gardiner TH, Banton MI, Tyler TR, Wright GA

BioTox for BP Chemicals, Inc., Richmond, Virginia, 23236-3465, USA.

The toxicity of isopropanol (IPA) has been extensively studied as a result
of a Test Rule under Section 4 of the Toxic Substances Control Act. In
general, the data showed that IPA has a low order of acute and chronic
toxicity; does not produce adverse effects on reproduction; is neither a
teratogen, a selective developmental toxicant, nor a developmental
neurotoxicant; and is not genotoxic or an animal carcinogen. IPA is,
however, a potential hazard for transient central nervous system depression
at high exposure levels. In addition, IPA produced effects to several
rodent toxicity endpoints at high dose levels (i.e., motor activity, male
mating index, and exacerbated renal disease) which are of
unclear relevance to human health. The data generated by these studies
confirmed that IPA acts as a typical short-chain alcohol in mammalian
biological systems. It produces a significant narcotic effect upon exposure
at high levels for extended periods of time, with no irreversible effects
even after repeated exposure, which is consistent with other  short-chain
alcohols. The metabolism of IPA appears equivalent across species with
rapid conversion to acetone andcarbon dioxide. Overall, these studies
demonstrate IPA exposure is a low potential hazard to human health. This
information will allow for an improved assessment of the human health risks
from IPA exposure.

Food Chem Toxicol 1992 Jul;30(7):631-4

Effects of isopropanol on the development of inflammatory
reactions in rats.

Kasuga F, Inoue S, Asano T, Kumagai S

Department of Biomedical Research on Food, National Institute of Health,
Tokyo, Japan.

The effects of isopropanol on the development of inflammation were studied
in rats. Isopropanol inhibited both the histamine-induced increase in
cutaneous vascular permeability and the carrageenan-induced plasma
exudation into the pleural cavity. The lipopolysaccharide-induced leucocyte
emigration into the subcutaneous pouch was unaffected by isopropanol, but
the leucocyte emigration of carrageenan-induced pleural inflammation was
markedly inhibited by isopropanol. In contrast, when isopropanol was
administered with an anti-inflammatory drug (indomethacin or
dexamethasone), it enhanced the pleural inflammatory reaction. These
results suggest that isopropanol may exert toxic effects through
interference with the normal processes of inflammation and interaction with
other agents that affect inflammatory reactions.

J Perinatol 1998 May-Jun;18(3):216-20

Isopropyl pad use in neonatal intensive care units.

Froman RD, Owen SV, Murphy C

Center for Nursing Research, School of Nursing, University of Connecticut,
Storrs 06269-2026, USA.

OBJECTIVES: Isopropyl pads (IPs) are commonly used to cleanse skin. This
traditional practice is benign when applied to adults, however, its
efficacy and safety when used for health-compromised neonates is
questionable. This research explores the extent of IP use in 114 infants in
neonatal intensive care units and identifies characteristics associated
with IP use. STUDY DESIGN: A descriptive design, with data collected at two
different sites over multiple observation periods, was used. RESULTS:
Generally low IP to skin use was found, with most babies being exposed to
one to two pads per 8 hours. Some babies, most frequently the lowest
weight, most premature, and health compromised babies, had exposure to as
many as eight pads per 8 hours. CONCLUSIONS: Because the smallest, most
vulnerable neonates are those most exposed to the highest levels of
isopropyl alcohol on the skin, conscious attention needs be paid to IP use
to avoid or eliminate unnecessary exposure to the potentially toxic

Fundam Appl Toxicol 1997 Apr;36(2):95-111

Isopropanol vapor inhalation oncogenicity study in Fischer 344 rats
and CD-1 mice.

Burleigh-Flayer H, Garman R, Neptun D, Bevan C, Gardiner T, Kapp R, Tyler
T, Wright G

Bushy Run Research Center/Union Carbide Chemicals and Plastics Company
Inc., Export, Pennsylvania 15632,

The potential oncogenic effects of isopropanol, a widely used solvent, were
investigated. Four groups of animals, each consisting of 75 CD-1 mice/sex
and 75 Fischer 344 rats/sex, were exposed to isopropanol vapor (CAS No.
67-63-0) at target concentrations of 0 (filtered air control), 500, 2500,
or 5000 ppm. Animals assigned to the core group (55 mice/sex/group and 65
rats/sex/group) were exposed for 6 hr/day, 5 consecutive days/week for at
least 78 weeks for the mice or 104 weeks for the rats. Ten mice/sex/group
and 10 rats/sex/group were assigned to an interim euthanasia group and were
terminated during Weeks 54 and 73, respectively. In addition, 10
mice/sex/group were assigned to a recovery group and did not receive any
further exposure following Week 53 but were retained until the core group
of animals was euthanized. Transient signs of narcosis were observed for
both mice and rats during exposure to 2500 and 5000 ppm and following
exposure for mice from the 5000-ppm group. Increased mortality (100% versus
82% for controls) and a decreased mean survival time (577 days versus 631
days for controls) were noted for male rats from the 5000-ppm group.
Increases in body weight and/or body weight gain were typically observed
for both sexes of mice
and rats from the 2500- and 5000-ppm groups throughout the study.
Urinalysis and urine chemistry changes indicative of impaired kidney
function (i.e., decreased osmolality and increased total protein, volume,
and glucose) were noted for male rats from the 2500-ppm group as well as
for male and female rats from the 5000-ppm group. At the interim
euthanasia, a concentration-related increase in testes weight (absolute and
relative as a percentage of body and brain weight) was observed for male
rats. Concentration-related increases in absolute and relative liver weight
(as a percentage of body weight) were observed for male and female mice. In
addition, increased absolute and/or relative (as
a percentage of body and brain weight) liver and kidney weights were
observed for male and/or female rats from the 2500- and 5000-ppm groups. At
necropsy, an increased incidence of seminal vesicle enlargement was
observed grossly for male mice from the 2500- and 5000-ppm groups.
Microscopically, some of the nonneoplastic lesions noted for mice included
an increased incidence of ectasia of the seminal vesicles for male mice
from the 2500- and 5000-ppm groups, minimal renal tubular proteinosis for
male and female mice from all isopropanol groups, and renal tubular
dilation for female mice from the 5000-ppm group. A number of nonneoplastic
lesions were observed for male and female rats from the 2500- and 5000-ppm
groups, with the most significant lesions being observed in the kidney and
associated with chronic renal disease. The lesions noted with increased
severity and/or frequency included mineralization, tubular dilation,
glomerulosclerosis, interstitial nephritis, interstitial fibrosis,
hydronephrosis, and transitional cell hyperplasia. The only tumor type
increased in incidence during the study was interstitial cell adenomas of
the testes in male rats. However, the increase in these adenomas was not
believed to be exposure-related due to an unusually low incidence observed
for the control group. There were no increased frequencies of neoplastic
lesions noted for male or female mice or for female rats from any
isopropanol exposure group. Chronic renal disease was attributed to be the
main cause of death for male and female rats from the 5000-ppm group and
was also considered to account for much of the mortality observed for male
rats from the 2500-ppm group. In conclusion, the no-observed-effect level
(NOEL) for toxic effects for both rats and mice was 500 ppm. The NOEL for
oncogenicity effects for both mice and rats was determined to be greater
than 5000 ppm.

Toxicol Appl Pharmacol 1996 Oct;140(2):235-44

Stimulated tissue repair prevents lethality in isopropanol-induced
potentiation of carbon tetrachloride hepatotoxicity.

Rao PS, Dalu A, Kulkarni SG, Mehendale HM

Division of Toxicology, College of Pharmacy and Health Sciences, Northeast
Louisiana University, Monroe 71209-0470, USA.

Published reports on the alcohol potentiation of CCl4 toxicity indicate
that in spite of enhanced hepatotoxicity there is no increase in lethality.
The objective of this study was to investigate the mechanism involved in
animal survival despite significantly enhanced liver injury. Male
Sprague-Dawley rats (175-225 g) were treated with isopropanol (ISOP, 2.5
ml/kg, 25% aqueous solution, po) 24 hr prior to CCl4 (1 ml/kg, ip)
administration. Plasma enzymes (ALT and SDH), hepatic glycogen levels, and
[3H]thymidine (3H-T) incorporation into hepatonuclear DNA were measured
during a time course (0-96 hr) after CCl4 administration. Liver sections
were examined for histopathology and cell cycle progression by
proliferating cell nuclear antigen (PCNA) immunohistochemistry. Maximum
injury was observed at 36 hr in both the groups as indicated by elevated
plasma enzyme levels and by histopathology. The extent of injury in the
ISOP + CCl4 group was higher than that in the H2O + CCl4 group. Plasma
enzyme activity returned to control levels by 60 hr, indicating recovery
from injury in both groups. Maximum 3H-T incorporation occurred at 48 hr in
both groups (ISOP + CCl4; vehicle + CCl4), indicating maximum stimulation
of S-phase synthesis. PCNA studies revealed a corresponding
stimulation of cell cycle progression. The wave of S-phase synthesis and
cell cycle progression returned to control levels in the H2O + CCl4 group
by 60 hr but continued up to 72 hr in the ISOP + CCl4 group. These findings
support the hypothesis that in response to increased infliction of CCl4
injury by isopropanol, augmented stimulation of cell division and tissue
repair restrain the progression of injury and restore hepatic structure and
function, thereby allowing the rats to survive. Further, antimitotic
intervention with colchicine (1 mg/kg, ip) led to decreased S-phase
synthesis, followed by 60% lethality in the isopropanol-pretreated group in
contrast to 40% lethality in the group receiving CCl4 alone (H2O + CCl4).
These findings suggest that greater stimulation of tissue repair restrains
the progression of ISOP-enhanced infliction of CCl4 liver injury and
accounts for recovery from enhanced liver injury and animal survival. The
findings are consistent with a two-stage model of toxicity wherein liver
injury is linked by progression or regression of injury, which is governed
by the extent of tissue repair to the final outcome.

Dr. Charles A. Miller III,   rellim at mailhost.tcs.tulane.edu
Dept. Environmental Health Sciences, SL29
Tulane-Xavier Center for Bioenvironmental Research and
Tulane Univ. School of Public Health and Tropical Medicine
1430 Tulane Ave.
New Orleans, LA 70112
(504)585-6942, fax (504)584-1726
Bionet.toxicology newsgroup: http://www.bio.net/hypermail/TOXICOLOGY

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