In the face of FDA warnings on how dangerous MMS and the chemical chlorine dioxide I have decided that this CDC study must be a part of our file. The first paragraph really says it all. If you have feared taking MMS thinking it is dangerous this study should alleviate some of those fears.
I forgot to save the original link for this PDF file. If anyone has it please post it again.
Environmental
Health Perspectives
Vol. 46, pp. 57-62, 1982
Controlled Clinical Evaluations of Chlorine Dioxide,
Chlorite and Chlorate in Man
by Judith R. Lubbers,*
Sudha Chauan,* and Joseph
R.
Bianchine*
To assess the
relative safety of chronically administered chlorine water disinfectants in man, a controlled study was undertaken. The clinical evaluation was conducted in the three phases common to investigational drug studies.
Phase I, a rising does tolerance investigation, examined the acute effects of progressively increasing single doses of chlorine disinfectants to normal healthy adult male volunteers.
Phase II considered the impact on normal subjects of daily ingestion of the disinfectants at a concentration of 5 mg/l. for twelve consecutive weeks. Persons with a low level of glucose-6-phosphate dehydrogenase may be expected to be especially susceptible to oxidative stress; therefore, in Phase III, chlorite at a concentration of 5 mg/l. was administered daily for twelve consecutive weeks to a small group of potentially at-risk glucose-6-phosphate dehydrogenase-deficient subjects.
Physiological impact was assessed by evaluation of a battery of qualitative and quantitative tests. The three phases of this controlled double-blind clinical evaluation of chlorine dioxide and its potential metabolites in human male volunteer subjects were completed uneventfully. There were no obvious undesirable clinical sequellae noted by any of the participating subjects or by the observing medical team.
In several cases, statistically significant trends in certain biochemical or physiological parameters were associated with treatment; however, none of these trends was judged to have physiological consequence. One cannot rule out the possibility that, over a longer treatment period, these trends might indeed achieve proportions of clinical importance. However, by the absence of detrimental physiological responses within the limits of the study, the relative safety of oral ingestion of chlorine dioxide and its metabolites, chlorite and chlorate, was demonstrated.
Introduction
Chlorine dioxide is currently under serious consideration in the United States as an alternative to chlorine water treatment. Before chlorine dioxide may be used routinely as a water disinfectant, the safety of oral human ingestion of chlorine dioxide and its
by-products must be assessed. For this purpose, a controlled clinical evaluation of chlorine dioxide, chlorite and chlorate was undertaken under the auspices of USEPA HERL #CR805643.
The study was conducted in three parts.
Phase I was designed to evaluate the acute physiological
(* The Department of Pharmacology, The Ohio State University,College
of Medicine, 333 W. 10th Avenue, Columbus, OH 43210) effects of progressively increasing doses of disinfectants administered to normal healthy adult males.
Chronic ingestion by normal male volunteers was studied in Phase II.
Phase III assessed the physiologicalresponse of a small group of potentially susceptible individuals, those deficient in glucose-6-phosphate dehydrogenase, to chronic ingestion of chlorite.
Methods
Subject
Selection
For Phase I and for Phase II, normal healthy adult male volunteers were selected. No prospective study participant who exhibited a significant abnormality in the routine clinical serum analysis, 58 blood count, urinalysis, or electrocardiogram was
selected. Subjects manifested no physical abnormalities at the pretreatment examination, were 21 to 35 years of age, and weighed within � 10% of normal body weight for their frame and stature. A history of disease or any medical or surgical condition which might interfere with the absorption, excretion, or metabolism of substances by the body precluded inclusion. Regular drug intake prior to the start of the investigation, either therapeutic or recreational, resulted in exclusion from the study.
Normal methemoglobin levels, thyroid function, and
glutathione levels were mandatory. Written informed
consent was obtained from each subject prior to initiation of treatment.
For Phase III, volunteers
were defined as glucose-6-phosphate dehydrogenase (G-6-PD)-deficient on the basis of a hemoglobin G-6-PD level of less than 5.0 IU/GM hemoglobin in the pre-study screening.
Phase III subjects were normal in all other respects.
Water Disinfectant Preparation
A detailed description of the water disinfectant preparation techniques has been presented by Lubbers and Bianchine (1).
In general, freshly prepared stock solutions of chlorine dioxide, sodium chlorite,
sodium chlorate, chlorine and chloramine were assayed by the colorimetric techniques of Palin (2) then diluted with organic-free demineralized deionized water to appropriate concentrations. Individual bottles were capped and stored in the dark under refrigeration until use. All bottles were coded by an independent observer and the identity of each bottle remained "double-blind" to both the investigative staff
and the volunteer subjects.
Study Design:
Phase I
The 60 volunteers in Phase I were divided at random into six treatment groups (1). Ten persons were assigned to receive each of the disinfectants; the ten members of the control group received untreated water. The study involved a series of six sequences of three days each. Treatment concentrations were increased for each treatment. The specific concentrations or disinfectant administered to the study participants are listed in Table 1. A clinical evaluation of the collection of blood and urine samples for determination of pretreatment baseline laboratory values preceded the first treatment.
On the first day of each three day treatment sequence, each volunteer ingested 1000 ml of the water in two portions. The second 500 ml portion aliquot was administered 4 hr after the first. Each 500 ml portion was consumed within 15 min. Only two doses of disinfectant were administered on the LUBBERS, CHAUAN AND BIANCHINE
first day of each treatment sequence. No disinfectant was administered on the second and third day of each sequence, since these two days were to serve as followup observation days. The second day of the treatment sequence consisted of a physical
examination and collection of blood and urine samplesfor determination of posttreatment laboratory values. On the third day, each volunteer was given
a physical examination to determine residual effects of treatment with the water disinfectants and byproducts.
Taste evaluations were obtained at each dose
level. Study participants were asked to rate the treated water as very unpleasant, slightly unpleasant,not pleasant, pleasant, or tasteless.
__________________
"first they ignore you
then they laugh at you
then they fight you
then you win".... Mahatma Ghanda
The sixty volunteers of Phase II were divided at random into six treatment groups of ten subjects each (3).
In order to assure efficient management of the 60 subjects, they were randomly
assigned to three subsets. These subsets were sequentially entered into the study
on three successive days and exited from this study in a similar fashion.
For all of the treatment groups, the concentration of disinfectants
ingested
was 5 mg/l. The control group received untreated water. Each subject received 500 ml daily for 12 weeks. Physicals, collection of blood and urine
samples for laboratory assays, and taste evaluations were conducted on a weekly basis
during the treatment period and for 8 weeks following cessation of treatment.
Study
Design: Phase III
The three glucose-6-phosphate dehydrogenasedeficient
subjects of Phase III were given sodium chlorite at a concentration of 5 mg/I. chlorite (4). The treatment protocol was identical to that of
Phase II, with daily administration of 500 ml ofsolution to each volunteer.
Evaluation Procedures
An extensive battery of parameters was monitored to assess the biochemical and physiological response to the oral ingestion of the water disinfec tants and water treatment by-products (Table 2).
All laboratory determninations of biochemical parameters were conducted by a licensed medical laboratory, Consolidated Biomedical Laboratories, Inc.
(CBL),
Columbus, Ohio, HEW license number
34-1030. For each volunteer, pretreatment baseline
values and six sets of posttreatment values were
compiled.
Laboratory tests were carefully chosen.
ORAL
INTAKE OF CHLORINE DISINFECTANTS IN MAN
Table 1. Concentration of disinfectants in phase I: acute rising dose tolerance.a
Disinfectant concentration, mg/l.
Water disinfectant
Day 1 Day 4 Day 7 Day 10 Day 13 Day 16
Chlorate
0.01 0.1 0.5 1.0 1.8 2.4
Water control 0 0
0 0 0 0
Chlorine dioxide
0.1 1.0 5.0 10.0 18.0 24.0
Chlorite 0.01 0.1 0.5
1.0 1.8 2.4
Chlorine 0.1 1.0
5.0 10.0 18.0 24.0
Chloramine
0.01 1.0 8.0 18.0 24.0
aFor
each dose, two portions of 500 ml each were administered at 4-hr intervals.
Table 2. Biochemical parameters assayed in the controlled clinical evaluation of chlorine dioxide, chlorite and chlorate in man.
Physical exam Systolic blood pressure, diastolic blood pressure, respiration rate, pulse rate, oral temperature aThese parameters yielded qualitative data only; no statistical analysis was performed.
On the basis of the literature (5-8), areas of suspected biochemical response to ingestion of chlorine oxidants were defined; a portion of the test battery was
specifically devoted to monitoring this response.
Red blood cell surface antibody formation was clinically
monitored by the qualitative Coombs test;
thyroid function by
T-3 (uptake), T-4 (RIA), and
free thyroxine; and response to oxidative stress by
glucose-6-phosphate
dehydrogenase, methemoglobin and glutathione levels. Hemoglobin electrophoresis
was used to detect possible hemoglobin abnormalities.
A battery of peripheral parameters was assayed
to provide supplementary information and to assist in evaluation of overall physiological well-being. The specific serum, blood and urine parameters
assayed have been discussed by Lubbers and Bianchine (1).
The numerical values obtained were collected and analyzed by utilizing the facilities of The Ohio State University Division of Computing Services for Medical Education and Research. Specially designed programs facilitated rapid clinical feedback.
Any value for an individual subject which differed from the group mean by more than two standard deviations was noted. In addition, every individual value which fell outside normal laboratory ranges for that parameter was designated as abnormal. Chemical parameters for volunteers who exhibited abnormal values were subjected to careful scrutiny; the safety and the possibility of hypersensitivity
to the disinfectant agents were evaluated for each of these individuals on a continuing basis throughout the study.
Statistical analyses utilized commercially available computer packages, specifically, the Biomedical Computer Programs (BMDP) and the StatisticalPackage for the Social Sciences (SPSS). Two-way analyses of variance with repeated measures utilized
BMDP2V. BMDP1R was used to perform multiple linear regression analyses.
For pairwise
t-tests and simple t-tests, SPSS-T-test was employed.
An important aspect of this study was the carefuland continued medical observation of all subjects.The general clinical histories and physical examinations
alone with subjective observations and qualitative
laboratory tests throughout this study were accumulated in each subject's medical file. A careful
50 60 inspection of each of these medical files presented areview of the general clinical health of each subject. The careful clinical evaluation of every subject in
Phases , II and III failed to reveal any clinically important impact upon the medical well-being of any subject as a result of disinfectant ingestion.
Further, there was no apparent grouping of the minor subjective symptoms and objective signs noted throughout the study; the "colds," "lymphadenopathy,"
"sore throats" and "flu" problems noted episodically appear to be randomly dispersed among the treatment groups. All subjects remained negative with respect to the Coombs tests and the sickle cell tests
during the investigation. Hemoglobin electrophoresis
results indicated that, in Phase II, a small number of subjects yielded abnormal hemoglobin distributions but these individuals were found to be
randomly distributed in both the treatment groups and
in the control group.
Examination of electrocardiograms revealed no abnormalities.Vital signs (blood pressure, pulse rate, respiration rate and body temperature) were measured on a
regular basis to provide immediate feedback to the monitoring physician on the acute physiologicalresponse of study participants to treatment. The statistical
analysis of the vital signs was limited to the calculation of arithmetic group means and standard deviations from the mean. The compiled vital signs were examined for evidence of consistent response to treatment. No such evidence was found.
The subjective evaluations of palatability
indicated that few subjects found the test substances to have an objectionable taste at levels up to 24 mg/l.
Several researchers have addressed the physiological
effects of oral ingestion of the oxidizing agents, chlorine dioxide, chlorite and chlorate. Musil et al. (9) associated oral chlorite ingestion with methemoglobin formation. In studies by Heffernan et al. (7,8), Abdel-Rahman et al. (5) and Couri et al.
(6), hemolytic anemia and suppressed glutathione
levels were observed in animals treated with chlorite.
The oral administration of chlorate to laboratory
animals has been shown to induce oxidative
destruction of hemoglobin and methemoglobin formation
(10, 11). The possibility of renal toxicity at
high levels of chlorite ingestion was suggested by
the increased kidney/body weight ratio reported by
Heffernan et al. (7). Haller and Northgraves (12)
and Fridlyand and Kagan (13) examined the chronic
toxicity of orally consumed chlorine dioxide in rats;
a slightly increased two-year mortality rate and a
decreased rate of weight gain were observed. Oral
administration of chlorite (14-16) to mice was shown
to increase mean corpuscular volume, osmotic fragility,
levels and red ell count (17). The maternal toxicity,
embryonic toxicity and the teratogenic potential
of concentrations of sodium chlorite was evaluated
in rats (18).
Unfortunately, the information available on the impact of chlorine dioxide, chlorite, and chlorate ingestion in man is severely limited. Epidemiological studies (19,20) have failed to conclusively identify any significant exposure related effects. The clinical evaluation described in this report was an attempt to elucidate the effects of the chlorite, chlorine dioxide and chlorate in man under controlled clinical conditions. During the course of the three-phase study, a massive volume of raw data was acquired. Routine rinalyses were performed and a meticulous exam-
61
62
LUBBERS, CHAUAN AND BIANCHINE
ination of this body of information was made. No
definitive finding of detrimental physiological impact
was made in any of the three phases of this human
investigation of the relative safety and tolerance of
oral chlorine disinfectant
ingestion. In several cases,
statistically significant trends were associated with treatment; however, none of these trends were judged to have immediate
physiological consequence. One cannot rule out the possibility that, over a longer treatment period, these trends might indeed
achieve proportions of clinical importance. However,
within the limits of the study, the relative safety of oral ingestion of chlorine dioxide and its metabolites,
chlorite and chlorate, was demonstrated by
the absence of
detrimental physiological response.
REFERENCES
1. Lubbers, J. R., and Bianchine, J. R. The effects of the acute rising dose administration of chlorine dioxide, chlorate and chlorite to normal healthy adult male volunteers. J.
Environ.
Pathol. Toxicol. 5 (2, 3): 865-878 (1982).
2. Palin, A. T. Methods for the
determination, in water of free
and
combined available chlorine, chlorine dioxide and chlorite, bromine, iodine and ozone, using diethyl-p-phenylenediamine (DPD). J. Inst. Water Engr. 21: 537-549 (1976).
3. Lubbers, J. R., Chauhan, S., Miller, J. K., and Bianchine, J.
R. The effects of chronic administration of chlorine dioxide, chlorite and chlorate to normal healthy adult male volunteers.
J. Environ. Pathol. Toxicol. 5 (2, 3): 879-888 (1982).
4.
Lubbers, J. R., Chauhan, S., Miller, J. K. and Bianchine, J. R. The effects of chronic administration of chlorite to glucose-6-phosphate dehydrogenase deficient healthy adult male volunteers. J. Environ. Pathol. Toxicol. 5 (2, 3):889-892 (1982).
5. Abdel-Rhaman, M. S., Couri, D., and Bull, R.J. Kinetics of
C102 and effects of C102, and C102, and C103 in drinking water on blood glutathione and hemolysis in rat and chicken.J. Environ. Path. Toxicol. 3(1,2): 431-449 (1979).
6. Couri, D., and Abdel-Rahman, M.S. Effect of chlorine
dioxide and metabolites on glutathione dependent system in rat, mouse and chicken blood. J. Environ. Pathol. Toxicol.3(1,2): 451-460 (1979).
7. Heffernan, W. P., Guion, C., and Bull, R. J. Oxidative damage to the erythrocyte induced by sodium chlorite in vitro. J. Environ. Pathol. Toxicol. 2(6): 1487-1499 (1979).
8.
Heffernan, W. P., Guion, C., and Bull, R. J. Oxidative damage to the
erythrocyte induced by sodium chlorite invitro. J. Environ. Pathol. Toxicol. 2(6): 1501-1510 (1979).
9. Musil, J., Kontek, Z., Chalupa, J., and Schmidt, P. Toxicological aspects of chlorine dioxide application for the treatment of water containing phenol. Chem. Technol. Praze. 8:327-345 (1964).
10. Richardson, A. P. Toxic potentialities of continued
administration of chlorate for blood and tissues. J.
Pharmacol. Exptl. Therap. 59: 101-103, (1937).
11. Jung, F., and Kuon, R. Zum inaktiven hemoglobin das
12. Haller, S. F., and Northgraves, W.W. Chlorine dioxide and
safety. TAPPI 33: 199-202 (1955).
13. Fridyland, S. A., and Kagan, G. Z. Experimental validation
of standards for residual chlorine dioxide
in drinking water. Hygiene Sanitation 36: 18-21 (1971).
14. Moore, G. S., and Calabrese, E. J. The effects of chlorine dioxide and sodium chlorite
on erythrocytes of A-J and C-57L-J mice. J. Environ. Pathol. Toxicol. 4(2, 3): 513-524 (1980).
15. Moore, G. S. and Calabrese, E. J. G-6-PD-deficiency-a potential
high-risk group to copper and chlorite ingestion. J. Environ. Pathol. Toxicol. 4(2, 3): 271-279 (1980).
16. Moore, G. S., Calabrese, E. J. and Ho, S. C. Groups at
potentially high-risk from chlorine dioxide treated water. J. Environ. Pathol. Toxicol. 4(2, 3): 465-470 (1980).
17. Berez, J. P., DiBiasi, D. L., Jones, L., Murray, D., and Boston, J.
Subchronic toxicity of alternate disinfectants and related compounds
in the non-human primate. Environ. Health Perspect. 46: 47-55 (1982).
18.
Couri, D., Miller, C. H., Bull, R. J., Delphia, J. M., and Ammar, E. M. Assessment of maternal toxicity, embryotoxicity and teratogenic potential of sodium chlorite in Sprague- Dawley
rats. Environ. Health Perspect. 46: 25-29 (1982).
19. Haring, B. J., and Zoetman, B. C. Corrosiveness of drinking water and cardiovascular diesase mortality. Bull. Environ. Contam. Toxicol. 25: 658-662 (1981).
20. Michael, G. E., Miday, R. K., Bercz, J. P., Miller, R Greathouse, D. G., Kraemer, D. F., and Lucas, J. B.
Chlorine dioxide
water disinfection: a prospective epidemiology. Arch. Environ. Health 36(1): 20-27 (1981).
CDC Contolled Trial of Chlorine Dioxide- pt1
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