AMRL-TR-64-106

PYRIDOXINE (VITAMIN B) TOXICITY6

LITERATURE REVIEW

ROBERT A. SCHNEIDER, CAPTAIN, USAF, MC, FSRESIDENT, AVIATION M i9OICINE, PHASE III

OCTOBER 1964

PHYSIOLOGY DIVISIONBIOMEDICAL LABORATORY

AEROSPACE MEDICAL RESEARCH LABORATORIESAEROSPACE MEDICAL DIVISIONAIR FORCE SYSTEMS COMMAND

WRIGHT-PATTERSON AIR FORCE BASE, OHIO

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700 - December 1964 - 448-16-411

PYRIDOXINE (VITAMIN B ) TOXICITY6LITERATURE REVIEW

ROBERT A. SCHNEIDER, CAPTAIN, USAF, MC, FSRESIDENT, AVIATION MEDICINE, PHASE III

FOREWORD

This literature review was performed at the suggestion of the Biomedical Lab-oratory of the Aerospace Medical Research Laboratories, Toxic Hazards Branch,Physiology Division, Wright-Patterson Air Force Base, Ohio, and in partialfulfillment of the Phase III requirements for residency in Aviation Medicine.Sponsors for this portion of the work were Dr. Anthony Thomas and Dr. KennethBack, Toxic Hazards Branch.

This technical report has been reviewed and is approved.

WAYNE H. McCANDLESTechnical DirectorBiomedical Laboratory

ii

ABSTRACT

The literature from 1940 through June 1963 was surveyed to summarize the datafrom pyridoxine toxicity studies in animals and to ascertain the highest dosesof pyridoxine (vitamin B6 analogs) that have been administered to human sub-jects as a therapeutic measure with no clinical evidence of toxicity.Analysis of the data indicated that doses of 25 mg/kg pyridoxine hydrochlorideshould be well tolerated as a therapeutic measure when required. In particular,pyridoxine hydrochloride can be used when required in the specific treatmentof a clinical entity such as acute UDMH intoxication.

iii

SECTION I

INTRODUCTION

The increased use of 1,1-dimethylhydrazine (UDMH) as a missile propellant inrecent years has necessitated numerous toxicological and pharmacologicalstudies of this compound to obtain information needed for diagnosis and treat-ment in the event of accidental UDMH exposure in man (refs 2, 3, 4, 16, 17,24, 25, 26, 36). These studies have also been useful in setting safethreshold limit values, and in establishing proper propellant handling pro-cedures.

Several of these investigations have shown that treatment with certainvitamin B6 analogs in high doses will prevent convulsions and death in variouslaboratory animals exposed to known lethal concentrations of UDMH (refs 3, 8,16, 24). The exact mechanism of this protection is not completely understood,but is believed to be primarily related to the function of pyridoxine as aco-enzyme for glutamic acid decarboxylase (GAD) and gamma aminobutyric acidtransaminase (GABAT), in the gamma aminobutyric acid (GABA) shunt of thetricarboxylic acid cycle within the central nervous system (refs 8, 16).

The dose of pyridoxine required to successfully treat animals exposed to highconcentrations of UDMH, as well as the suggested emergency treatment dose forseverely exposed humans (ref 3), is much higher than the dose normally used inclinical practice. The purpose of this study is to briefly summarize pyridox-ine toxicity studies in animals and to review the reported clinical uses ofpyridoxine in high and/or prolonged doses in man, with regard to its possibletoxic effects.

SECTION II

ANIMAL TOXICITY STUDIES

Few pyridoxine toxicity studies in animals have been reported in the litera-ture (refs 3, 34, 35, 37). The results of these studies are summarized intables I and II.

TABLE I

SUMMARY OF ACUTE TOXICITY STUDIESOF

PYRIDOXINE IN LABORATORY ANIMALS

Investi- Route ofgator & Compound Adminis- LD5 0 Dose Death

Animal Date Tested tration mg/kg rime from Dose*

Rats Unna Pyridoxine Subcutan- 3700 36-72 hr1940 Hydrochlor- eous

ide

Unna Oral 5500-6000 36-72 hr1940

Weigand iv 657 5 min1940

Mice Weigand Pyridoxine iv 545 5 min1940 Hydrochlor-

ide

Back Pyridoxa- ip 2100 24 hr1963 mine dihy-

drochloride

*Convulsions occurred before death under each condition.

2

TABLE II

SUMMARY OF CHRONIC TOXICITY STUDIESOF

PYRIDOXINE IN LABORATORY ANIMALS

Investi- Route ofgator & Compound Adminis- Dosage Duration*

Animal Date Tested tration mg/kg/day Days

Rats Unna Pyridoxine Oral 20 801940 hydrochlor-

ide

Mice Weigand iv 100 141940

Dogs Unna Oral 20 801940

Monkeys Unna Oral 10 391940

Monkeys Unna Subcu- 10 1061940 taneous

*No clinical or pathological changes occurred subsequent to administration.

These data imply that pyridoxine toxicity, either acute or chronic, is rela-tively low in the species studied. Extrapolation of these findings to theclinical use of pyridoxine in humans suggests that a wide margin of safetyexists between normal therapeutic doses and doses high enough to cause signsand symptoms of pyridoxine toxicity.

3

SECTION III

CLINICAL EXPERIENCE WITH MAN

Common Use and Dosage

Aside from its inclusion in small amounts in multivitamin preparations and itsuse in vitamin B6 deficiencies, pyridoxine has been used in the treatment ofmany disorders for which no specific therapy is available, and in which theindications for pyridoxine are not well established. These include disorderssuch as the nausea and vomiting associated with pregnancy, motion sickness,post-anesthesia, and post-irradiation; acute alcoholic intoxication anddelirium tremens; various dermatoses; anemias of certain types; and a varietyof neuromuscular and neurological conditions.

The vitamin B6 analog used almost exclusively in clinical practice is pyri-doxine hydrochloride, since it is the form normally available to physicians.The usual adult doses range from 25 to 100 mg (occasionally up to 250 mg)daily, given either orally or parenterally. For a man weighing 70 kg, thisis a dose range of 0.35 to 3.5 mg/kg/day.

Recommend Use in Acute UDMH Intoxication

To date, no human exposures to UDMH severe enough to cause convulsions havebeen reported, and pyridoxine in high doses has never been used for the treat-ment of acute UDMH toxicity in humans. Back, Pinkerton, and Thomas (ref 3)have recently recommended that an initial dose of pyridoxine hydrochloride of25 mg/kg (25% given iv and 75% im) be administered parenterally at the firstsign of significant UDMH toxicity (usually nausea or vomiting or both). Theysuggest a second dose of 25 mg/kg if convulsions occur and are at all severeor persistent.

Reported Clinical Use In High and/or Prolonged Doses

The literature from 1940 through June 1963 was surveyed. Twenty-four papers(11 U.S. and 13 foreign) were found in which were reported pyridoxine dosesand/or duration of treatment to a degree sufficient to warrant inclusion inthis review.

Only abstracts of the foreign papers were reviewed (these are noted in thelist of references). Many of the U.S. papers reviewed in complete form didnot contain all of the desired data, ie, numbers of subjects, ages, weights,sex, exact pyridoxine dose, routes, frequency and duration of administration,or methods used in evaluating possible toxic effects of pyridoxine. Thepurpose of the majority of articles reviewed was to evaluate the effectivenessof pyridoxine in various disorders, and not to study possible toxic sideeffects of the drug. Most of the 651 subjects reported in the 24 articles hadactive disease processes giving rise to a variety of symptoms, and positivephysical examination and laboratory findings, all of which would complicatethe detection of pyridoxine toxic effects were they to occur.

To aid in comparing the findings in these articles, the data were used tocompute the milligram dose of pyridoxine per kilogram of body weight for each

4

study. The data available for these computations varied among the articlesin completeness and specificity. The criteria used to calculate these mg/kgdoses are given in table III. Accuracy of the computed mg/kg doses isbelieved to be reasonably reliable. The significant findings, including thecalculated mg/kg doses, are given in table IV.

As shown in table IV, some subjects received large doses of pyridoxine in termsof usual clinical doses. However, harmful or toxic effects from the drug werenot reported in any of the studies.

To determine the numbers of subjects receiving the drug, in single or totaldaily doses, at various dose levels, and by various routes, the data from the24 studies were used as shown in table V. This information is helpful inregard to the relative safety of giving pyridoxine in high doses over a shortperiod of time. The numbers of subjects are given cumulatively.

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TABLE V

CUMULATIVE NUMBERS OF SUBJECTS RECEIVING PYRIDOXINE(SINGLE OR TOTAL DAILY DOSES) AS nag/kg DOSE LEVELS

AND BY VARIOUS ROUTES OF ADMINISTRATION

Dose mg/kg* Cumulative Numbers of Subjects

Levels (single Route of Administrationor total daily All Parenteral _

dose) Subjects Unknown Oral - UTotal iv i~m Unknown

30 + 1 - 1 1 -20 + 4 3 1 1 -

15 + 7 3 - 4 3 1 -13 + 190 38 1 151 6 1 1411 + 191 38 1 152 7 1 144

9 + 191 38 1 152 7 1 147 + 422 154 55 233 31 1 2015 + 564 154 93 317 31 1 2853 + 597 160 93 344 39 9 2961 + 623 186 93 344 39 9 296

< 1 651 200 93 358 53 9 296

*mg/kg dose levels as computed in table IV.

The relative safety of giving pyridoxine at various dose levels is probablya lesser problem than short-term high dose safety. However, the dataobtained in this review have been examined in terms of duration of treat-ment, various dose levels, and numbers of subjects. This cumulative infor-mation is given in table VI.

9

TABLE VI

CUMULATIVE NUMBERS OF SUBJECTS RECEIVING PYRIDOXINEBY DURATION OF TREATMENT AT VARIOUS mg/kg DOSAGE LEVELS

Dose mg/kg* Cumulative Numbers of Subjects

Levels (singleor total daily All Duration of Treatment (in days)

dose) Subjects <1 1-4 5-9 10-19 20-29 30+ Unknown

30+ 1 1 - - - - -

20+ 4 1 - - - - 3 -

15... 7 4 - - - - 3 -13+ 190 151 - - - - 4 35ll+ 191 152 - - - - 4 35

9+ 191 152 - - - - 4 357+ 442 156 - 47 50 12 23 1545+ 564 156 46 47 126 12 23 154

3+ 597 156 46 47 126 28 23 1711+ 623 156 46 47 126 33 44 171

<1 651 170 46 47 126 33 44 185

*mg/kg dosage levels as computed in table IV.

SECTION IV

CONCLUSION

A review of pyridoxine toxicity studies in animals suggests that both acuteand chronic toxicity are relatively low in the species studied. This impliesthe existence of a very wide margin of safety between normal therapeuticdoses and doses high enough to cause signs and symptoms of pyridoxine toxicity.

Analysis of the data on the clinical use of pyridoxine at high and/or prolongeddoses suggests that pyridoxine toxicity, both acute and chronic, is low forman. It seems reasonable to believe that pyridoxine hydrochloride can be usedsafely in doses much higher than the usual clinical doses when required in thespecific treatment of a clinical entity such as acute UDMH intoxication.

10

LIST OF REFERENCES

1. Atkinson, G. W. and W. C. Kappes: "Pyridoxine (Vitamin B6 ) in Alcoholism,"Virginia Med. Mo. 83: 391-93, September 1956.

2. Back, K. C., M. Pinkerton, A. Cooper and A. A. Thomas: "Absorption,Distribution, and Excretion of 1,1-Dimethylhydrazine," Toxicol. ApplPharmacol. 5: 401-13, 1963.

3. Back, K. C., M. K. Pinkerton and A. A. Thomas: Therapy of Acute UDIHIntoxication, AMRL-TDR-63-44 (AD 411 759), Aerospace Medical ResearchLaboratories, Wright-Patterson Air Force Base, Ohio, June 1963.

4. Back, K. C. and A. A. Thomas: "Pharmacology and Toxicology of1,1-Dimethylhydrazine (UDMH)," Am. Ind. Hyg. Assoc. J. 24: 23-27, 1963.

5. Biehl, J. P. and R. W. Vilter: "Effect of Isoniazid on Vitamin B6Metabolism; Its Possible Significance in Producing Isoniazid Neuritis,"Proc Soc Exp Biol Med 85: 389-92, March 1954.

6. Briskas, S, F. Delbarre and P. Desgrez: "Action of Pyridoxine on BloodSugar in Normal Subjects and in Some Pathological Conditions," ComptRend Soc Biol 140: 400-2, 1946 (Abstract).

7. Buccellato, T. and P. Gismondo: "Clinical Observations of an Anti-Galactogenic Effect of Large Doses of Vitamin B6," Sicilia Sanit 3/7:15-22, Palermo 1950 (Abstract).

8. Dubnick, B., G. A. Leeson, and C. C. Scott: "Effect of Forms of VitaminB6 on Acute Toxicity of Hydrazines," Toxicol Appl Pharmacol 2: 403-9,1960.

9. Engelhardt-G~lkel, A., W. Seitz, and I. Woller: "Effect of Pyridoxineand Pyridoxal Phosphate on the Deamination of Glutamic Acid in Man,"Klin Wschr 36/9: 409-11, 1958 (Abstract).

10. Ewing, J. A., "The First Phase of Alcohol Rehabilitation. Report of aControlled Study with Benactyzine, Paraldehyde, and Pyridoxine,"Quart J. Studies Alcohol ZI: 68-81, 1960.

11. Finke, H., "Treatment of the Parkinsonian Syndrome with Large Doses ofVitamin B6," Mtnch Med Wochensch 96: 637-39, 1954 (Abstract).

12. Hyatt, H., "Acute Poisoning from Overdose of Isoniazid," Amer. J. DisChild 102: 228-32, 1962.

13. Korlin, R., "Effect of Pyridoxine Administration on the Vitamin B6 Activityof Human Milk," Bull. Soc. Chem Biol (Paris) 41: 1085-91, 1959 (Abstract).

11

14. Lebon, Jr., Claude R., M. Leutenegger, F. Gantz, P. Galley and J. Tricoire:"Vitamin B6 Deficiency in Diabetes: Possible Role in Producing Degener-ative Complications," Presse Med 69: 230-32, 1961 (Abstract).

15. McGeer, E. G. and B. Tischler: "Vitamin B6 and Mental Deficiency. TheEffects of Large Doses of B6 (Pyridoxine) in Phenylketonuria," CanadianJ. Biochem, 37/3: 485-91, 1959.

16. Meyers, F., F. Weir, G. Eisenlord, and J..Nemenzo: "Neuropharmacology ofHydrazine, UDMH, and Pentaborane," The Hine Labs Inc., sponsored by theAdvanced Research Projects Agency, DOD, April 1963.

17. Mitz, M., F. Aldrich, and B. Vasta: Study of the Intermediary MetabolicPathways of 1,1-Dimethylhydrazine, AMRL-TDR-62-110 (AD 290 509),Aerospace Medical Research Laboratories, Wright-Patterson Air Force Base,Ohio, September 1962.

18. Montenro, P.: "Pyridoxine and Diabetes," Acta Vitaminol 15: 55-60, 1961,(Abstract).

19. Palmer, E. J.: "Pyridoxine HC1 in the Treatment of Acute Alcoholism andDelirium Tremens," Virginia Med Mo 85: 15-16, 1955.

20. Pena, J., "The Therapeutic Effect of Large Amounts of Vitamin B6 onHemiconvulsive and Hemiplegic Syndromes and Their Sequelae," Rev EspanolaPediat 16: 385-92, 1960 (Abstract).

21. Peters, U. H. and H. Neumann: "Vitamin B6 Deficiency in Delirium Tremens,"Arch Psychiat Nervenkrankh 201: 165-72, 1960.

22. Popova, D. N.: "Beneficial Effect of Vitamin B6 on Blood Picture and Weightin Children with Signs of Hypotrophy and Secondary Anemia," Vop Pitan20/6: 37-40, Pediat Med Inst., Leningrad 1961 (Abstract).

23. Parcelli, T.: "Therapeutic Actions of Certain Vitamins of the B Complexand of Embryo Preparations in Infantile Erythrodermia Desquamativa,"Pediatria 60: 56-62, 1952 (Abstract).

24. Reeves, J. L.: "Influence of Large Doses of Pyridoxine Hydrochloride onthe Convulsive Activity of UDMH in Monkeys," SAM Report No. 62-31, USAFAerospace Med. Ctr, Brooks Air Force Base, Texas, December 1961.

25. Reynolds, H., F. Rohles, V. Caster, H. Brunson, J. Prine, K. Back andA. Thomas: The Effect of UDMH Injection on Complex Avoidance Behaviorin the Java Monkey, AMRL-TDR-63-39 (AD 410-933), Aerospace MedicalResearch Laboratories, Wright-Patterson Air Force Base, Ohio, May 1963.

26. Reynolds, H., F. Rohles, J. Fineg, K. Back and A. Thomas: The Effect ofUDMH Injection on Learned Behavior in the Java Monkey, AMRL-TDR-62-64

(AD 283 846), Aerospace Medical Research Laboratories, Wright-PattersonAir Force Base, Ohio, June 1962.

12

27. Roab, S., A. Hant, G. Cartwright, and M. Wintrobe: "Pyridoxine-ResponsiveAnemia," Blood 18: 285-302, 1961.

28. Schreiner, A. W., E. Rockwell and R. W. Vilter: "A Local Defect in theMetabolism of Pyridoxine in the Skin of Persons with Sebarrheic Dermatitisof the Sicca Type," J. Invest Dermatol 19: 95-6, 1952.

29. Scriver, C. R., "Vitamin B6 - Dependency and Infantile Convulsions,"Pediatrics 26: 62-74.

30. Small, M. D., N. Zamcheck, J. J. Votale, A. Longarim, and B. Fisher: "TheEffect of Pyridoxine Hydrochloride in Acute Alcoholic Intoxication,"J. Lab Clin Med 46: 12-20, 1955.

31. Stefanini, M. and G. Roi: "Preliminary Results of Treatment of Post-encephalitic Parkinsonism with Pyridoxine," Gazzetta Sanitaria 19/7-8:171-73, 1948 (Abstract).

32. Suarez, M.1: "Treatment of Whooping Cough, with Special Reference to theUse of Vitamin B6 in the Central Syndrome," Rev Espanola Pediat 14:77-83, 1958 (Abstract).

33. Suarez,, M., J. Teijeira, and G. Sierra: "Clinical and Bio-electric Studyof the Action of Vitamin B6 in Congenital Encephalopathy," Rev EspanolaPediat 14: 57-62, 1958 (Abstract).

34. Unna, K.: "Studies on the Toxicity and Pharmacology of Vitamin B6 ,"J. Pharmacol 70: 400-7, 1940.

35. Unna, K and W. Antopol: "Toxicity of Vitamin B6," Proc. Soc. Exp. BiolMed 43: 116-18, 1940.

36. Weeks, M.,.G. Maxey, M. Sicks and E. Greene: "Vapor Toxicity of UD1H inRats and Dogs from Short Exposures," Am. Ind. Hyg Assoc J 24: 137-43,1963.

37. Weigand, C., C. Eckler and K. Chen: "Action and Toxicity of Vitamin B6Hydrochloride," Proc Soc Eicp Biol Med 44: 147-51, 1946.

13

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Command, Wright-Patterson Air Force Base, Ohio N/A3. REPORT TITLE

PYRIDOXINE (VITAMIN B6 ) TOXICITY LITERATURE REVIEW

4. DESCRIPTIVE NOTES (Type of report end inclusive dates)

Review (literature from 1940 through June 1963)5. AUTHOR(S) (Last name, first name, initial)

Schneider, Robert A., Captain, USAF, MC, FS

6. REPORT DATE 78. TOTAL NO OF PAGES 7b. NO. OF REFS

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for residency in Aviation Medicine. Systems Command, Wright-Patterson AFB, 0.

13. ABSTRACT

The literature from 1940 through June 1963 was surveyed to summarize the data frompyridoxine toxicity studies in animals and to ascertain the highest doses ofpyridoxine (vitamin B6 analogs) that have been administered to human subjects as atherapeutic measure with no clinical evidence of toxicity. Analysis of the dataindicated that doses of 25 mg/kg pyridoxine hydrochloride should be well toleratedas a therapeutic measure when required. In particular, pyridoxine hydrochloride canbe used when required in the specific treatment of a clinical entity such as acuteUDMH intoxication.

DD , JAN64 1473 UNCLASSIFIEDAF-WP--AUG " 400 Security Classification

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14. KEY • LINK A LINK 8 LINK CKEY WORDS -

ROLE WT ROLE WT ROLE Wr

Toxicity, toxicologyPharmacologyPyridoxineDosage, biologyToxic tolerances, toxicologyVitamin B complex, pyridoxineAnimalsMan1, l-dimethylhydrazine (UDMH) toxicity

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or short phrases that characterize a report and may be used as9a. ORIGINATOR'S REPORT NUMBER(S): Enter the offi- index entries for cataloging the report. Key words must becial report number by which the document will be identified selected so that no security classification is required. Identi-and controlled by the originating activity. This number must fiers, such-as equipment model designation, trade name, militarybe unique to this report. project code name, geographic location, may be used as key9b. OTHER REPORT NUMBER(S): If the report has been words but will be followed by an indication of technical con-assigned any other repcrt numbers (either by the originator text. The assignment of links, rules, and weights is optional.or by the sponsor), also enter this number(s).

10. AVAILABILITY/LIMITATION NOTICES: Enter any lim-itations on further dissemination of the report, other than those

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