TOXICOLOGICAL PROFILE FOR

GUTHION

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry

September 2008
GUTHION ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 
GUTHION iii 

UPDATE STATEMENT 

A Toxicological Profile for Guthion, Draft for Public Comment was released in September 2006. This 

edition supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch 

1600 Clifton Road NE 

Mailstop F-32 

Atlanta, Georgia 30333 
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GUTHION v 

FOREWORD 

This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for the hazardous substance described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a hazardous substance’s toxicologic properties. Other pertinent 

literature is also presented, but is described in less detail than the key studies. The profile is not intended 

to be an exhaustive document; however, more comprehensive sources of specialty information are 

referenced. 

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile 

begins with a public health statement that describes, in nontechnical language, a substance’s relevant 

toxicological properties. Following the public health statement is information concerning levels of 

significant human exposure and, where known, significant health effects. The adequacy of information to 

determine a substance’s health effects is described in a health effects summary. Data needs that are of 

significance to protection of public health are identified by ATSDR and EPA. 

Each profile includes the following: 

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) A determination of whether adequate information on the health effects of each substance 

is available or in the process of development to determine levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identification of toxicologic testing needed to identify the types or 

levels of exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, and 

local levels; interested private sector organizations and groups; and members of the public. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Howard Frumkin M.D., Dr.P.H. Julie Louise Gerberding, M.D., M.P.H. 

Director Administrator 

National Center for Environmental Health/ Agency for Toxic Substances and 

Agency for Toxic Substances and Disease Registry 

Disease Registry 
GUTHION vi 

*Legislative Background 

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization 

Act (SARA) of 1986 (Public Law 99 499) which amended the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to 

prepare toxicological profiles for hazardous substances most commonly found at facilities on the 

CERCLA National Priorities List and that pose the most significant potential threat to human health, as 

determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous 

substances was announced in the Federal Register on December 7, 2005 (70 FR 72840). For prior 

versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); 

October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); 

October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 FR 9486); 

April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999(64 FR 56792); 

October 25, 2001 (66 FR 54014) and November 7, 2003 (68 FR 63098). Section 104(i)(3) of CERCLA, 

as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on 

the list. 
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QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)? 

Section 3.7 Children’s Susceptibility 

Section 6.6 Exposures of Children 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 
GUTHION viii 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
GUTHION ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Nickolette Roney, M.P.H. 

Selene Chou, Ph.D. 

Yee-Wan Stevens, M.S. 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA 

Antonio Quinones-Rivera, Ph.D. 

David Wohlers, Ph.D. 

Mario Citra, Ph.D. 

Syracuse Research Corporation, North Syracuse, NY 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3. Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4. Green Border Review. Green Border review assures the consistency with ATSDR policy. 
GUTHION x 

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PEER REVIEW 

A peer review panel was assembled for guthion. The panel consisted of the following members: 

Draft for Public Comment: 

1. Dr. Allan Flesot, Professor and Extention Specialist, Entomology and Environmental Toxicology, 

Food and Environmental Quality Lab, Washington State University-TriCities, Richland, 

Washington; 

2. Dr. Maryce Jacobs, President, Health Science Institute, Inc., Las Cruces, New Mexico; and 

3. Dr. Craig Wheelock, Junior Faculty, Microbiology and Tumorbiology Center, Karolinska 

Institute, Stockholm, Sweden. 

These experts collectively have knowledge of guthion's physical and chemical properties, toxicokinetics, 

key health end points, mechanisms of action, human and animal exposure, and quantification of risk to 

humans. All reviewers were selected in conformity with the conditions for peer review specified in 

Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as 

amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 
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CONTENTS 

DISCLAIMER .............................................................................................................................................. ii 

UPDATE STATEMENT ............................................................................................................................. iii 

FOREWORD ................................................................................................................................................ v 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS .................................................................... vii 

CONTRIBUTORS ....................................................................................................................................... ix 

PEER REVIEW ........................................................................................................................................... xi 

CONTENTS ............................................................................................................................................... xiii 

LIST OF FIGURES .................................................................................................................................. xvii 

LIST OF TABLES ..................................................................................................................................... xix 

1. PUBLIC HEALTH STATEMENT .......................................................................................................... 1 

1.1 WHAT IS GUTHION?................................................................................................................... 1 

1.2 WHAT HAPPENS TO GUTHION WHEN IT ENTERS THE ENVIRONMENT? ..................... 2 

1.3 HOW MIGHT I BE EXPOSED TO GUTHION? .......................................................................... 3 

1.4 HOW CAN GUTHION ENTER AND LEAVE MY BODY? ....................................................... 3 

1.5 HOW CAN GUTHION AFFECT MY HEALTH? ........................................................................ 4 

1.6 HOW CAN GUTHION AFFECT CHILDREN? ........................................................................... 4 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO GUTHION? ....................... 5 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED 

TO GUTHION? .............................................................................................................................. 5 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? .................................................................................................... 5 

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................... 6 

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 9 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO GUTHION IN THE 

UNITED STATES .......................................................................................................................... 9 

2.2 SUMMARY OF HEALTH EFFECTS ......................................................................................... 10 

2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 13 

3. HEALTH EFFECTS .............................................................................................................................. 25 

3.1 INTRODUCTION ........................................................................................................................ 25 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................... 25 

3.2.1 Inhalation Exposure .............................................................................................................. 26 

3.2.1.1 Death .............................................................................................................................. 26 

3.2.1.2 Systemic Effects ............................................................................................................. 27 

3.2.1.3 Immunological and Lymphoreticular Effects ................................................................ 27 

3.2.1.4 Neurological Effects ...................................................................................................... 32 

3.2.1.5 Reproductive Effects ...................................................................................................... 32 

3.2.1.6 Developmental Effects ................................................................................................... 33 

3.2.1.7 Cancer ............................................................................................................................ 33 

3.2.2 Oral Exposure ........................................................................................................................ 33 

3.2.2.1 Death .............................................................................................................................. 33 

3.2.2.2 Systemic Effects ............................................................................................................. 34 

3.2.2.3 Immunological and Lymphoreticular Effects ................................................................ 53 

3.2.2.4 Neurological Effects ...................................................................................................... 54 

3.2.2.5 Reproductive Effects ...................................................................................................... 55 

3.2.2.6 Developmental Effects ................................................................................................... 56 

3.2.2.7 Cancer ............................................................................................................................ 57 
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3.2.3 Dermal Exposure...................................................................................................................58 

3.2.3.1 Death..............................................................................................................................58 

3.2.3.2 Systemic Effects.............................................................................................................61 

3.2.3.3 Immunological and Lymphoreticular Effects ................................................................61 

3.2.3.4 Neurological Effects ......................................................................................................61 

3.2.3.5 Reproductive Effects......................................................................................................63 

3.2.3.6 Developmental Effects...................................................................................................63 

3.2.3.7 Cancer ............................................................................................................................64 

3.3 GENOTOXICITY........................................................................................................................64 

3.4 TOXICOKINETICS.....................................................................................................................64 

3.4.1 Absorption.............................................................................................................................64 

3.4.1.1 Inhalation Exposure .......................................................................................................64 

3.4.1.2 Oral Exposure ................................................................................................................68 

3.4.1.3 Dermal Exposure ...........................................................................................................68 

3.4.2 Distribution ...........................................................................................................................68 

3.4.2.1 Inhalation Exposure .......................................................................................................68 

3.4.2.2 Oral Exposure ................................................................................................................69 

3.4.2.3 Dermal Exposure ...........................................................................................................69 

3.4.3 Metabolism............................................................................................................................69 

3.4.4 Elimination and Excretion.....................................................................................................72 

3.4.4.1 Inhalation Exposure .......................................................................................................72 

3.4.4.2 Oral Exposure ................................................................................................................73 

3.4.4.3 Dermal Exposure ...........................................................................................................73 

3.4.4.4 Other Routes of Exposure..............................................................................................74 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models .............74 

3.5 MECHANISMS OF ACTION .....................................................................................................77 

3.5.1 Pharmacokinetic Mechanisms...............................................................................................77 

3.5.2 Mechanisms of Toxicity........................................................................................................77 

3.5.3 Animal-to-Human Extrapolations.........................................................................................79 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS.............................79 

3.7 CHILDREN’S SUSCEPTIBILITY..............................................................................................80 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT.......................................................................82 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Guthion............................................83 

3.8.2 Biomarkers Used to Characterize Effects Caused by Guthion..............................................84 

3.9 INTERACTIONS WITH OTHER CHEMICALS .......................................................................85 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .............................................. 86 

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................. 87 

3.11.1 Reducing Peak Absorption Following Exposure...............................................................87 

3.11.2 Reducing Body Burden .....................................................................................................88 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects............................................88 

3.12 ADEQUACY OF THE DATABASE.......................................................................................89 

3.12.1 Existing Information on Health Effects of Guthion ..........................................................89 

3.12.2 Identification of Data Needs..............................................................................................91 

3.12.3 Ongoing Studies ................................................................................................................99 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................101 

4.1 CHEMICAL IDENTITY............................................................................................................101 

4.2 PHYSICAL AND CHEMICAL PROPERTIES.........................................................................101 
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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................105 

5.1 PRODUCTION ..........................................................................................................................105 

5.2 IMPORT/EXPORT ....................................................................................................................105 

5.3 USE ............................................................................................................................................107 

5.4 DISPOSAL.................................................................................................................................108 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................109 

6.1 OVERVIEW...............................................................................................................................109 

6.2 RELEASES TO THE ENVIRONMENT...................................................................................111 

6.2.1 Air .......................................................................................................................................111 

6.2.2 Water...................................................................................................................................112 

6.2.3 Soil ......................................................................................................................................113 

6.3 ENVIRONMENTAL FATE ......................................................................................................113 

6.3.1 Transport and Partitioning...................................................................................................113 

6.3.2 Transformation and Degradation ........................................................................................117 

6.3.2.1 Air................................................................................................................................117 

6.3.2.2 Water............................................................................................................................117 

6.3.2.3 Sediment and Soil ........................................................................................................120 

6.3.2.4 Other Media .................................................................................................................121 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT.................................. 123 

6.4.1 Air .......................................................................................................................................123 

6.4.2 Water...................................................................................................................................124 

6.4.3 Sediment and Soil ...............................................................................................................126 

6.4.4 Other Environmental Media................................................................................................128 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE........................................128 

6.6 EXPOSURES OF CHILDREN..................................................................................................131 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ..............................................138 

6.8 ADEQUACY OF THE DATABASE ........................................................................................139 

6.8.1 Identification of Data Needs ...............................................................................................141 

6.8.2 Ongoing Studies ..................................................................................................................144 

7. ANALYTICAL METHODS ...............................................................................................................145 

7.1 BIOLOGICAL MATERIALS....................................................................................................145 

7.2 ENVIRONMENTAL SAMPLES ..............................................................................................148 

7.3 ADEQUACY OF THE DATABASE ........................................................................................149 

7.3.1 Identification of Data Needs ...............................................................................................149 

7.3.2 Ongoing Studies ..................................................................................................................152 

8. REGULATIONS AND ADVISORIES ...............................................................................................155 

9. REFERENCES ....................................................................................................................................159 

10. GLOSSARY ......................................................................................................................................177 
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APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1 

B. USER’S GUIDE.................................................................................................................................. B-1 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1 

D. INDEX ................................................................................................................................................D-1 
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LIST OF FIGURES 

3-1. Levels of Significant Exposure to Guthion – Inhalation .................................................................... 30 

3-2. Levels of Significant Exposure to Guthion – Oral ............................................................................. 47 

3-3. Proposed Metabolism of Guthion.......................................................................................................70 

3-4. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance......................................................................................................76 

3-5. Existing Information on Health Effects of Guthion............................................................................90 

6-1. Frequency of NPL Sites with Guthion Contamination.....................................................................110 
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LIST OF TABLES 

3-1. Levels of Significant Exposure to Guthion - Inhalation ..................................................................... 28 

3-2. Levels of Significant Exposure to Guthion - Oral .............................................................................. 35 

3-3. Levels of Significant Exposure to Guthion - Dermal ......................................................................... 59 

3-4. Genotoxicity of Guthion In Vivo ........................................................................................................65 

3-5. Genotoxicity of Guthion In Vitro .......................................................................................................66 

4-1. Chemical Identity of Guthion ...........................................................................................................102 

4-2. Physical and Chemical Properties of Guthion ..................................................................................103 

5-1. Manufacturers of Technical-Grade or Formulated Products Containing Guthion ...........................106 

6-1. Soil Adsorption Characteristics of Guthion in Five European Soils ................................................115 

6-2. Aqueous Degradation Rate of Guthion.............................................................................................119 

6-3. Soil Properties and Degradation Rate of Guthion in Four Italian Soils............................................122 

6-4. Guthion Levels in Surface Water from the STORET Database .......................................................127 

6-5. Guthion Residues in Various Foods from 1994 to 2000 ..................................................................129 

6-6. Selected Percentile Urine Concentrations (μg/L) of DMP in the U.S. Population from

1999 to 2002.....................................................................................................................................132 

6-7. Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of DMTP in the 

U.S. Population from 1999 to 2002..................................................................................................133 

6-8. Selected Percentile Urine Concentrations (μg/L) of DMDTP in the U.S. Population from

1999 to 2002.....................................................................................................................................134 

6-9. Dietary Average Daily Intake of Guthion (μg/kg/day).....................................................................135 

6-10. Excretion of DMTP Following the Dermal Application of Guthion to Volunteers .......................140 

7-1. Analytical Methods for Determining Guthion and Various Metabolites in Biological Samples .....147 

7-2. Analytical Methods for Determining Guthion in Environmental Samples ......................................150 

8-1. Regulations and Guidelines Applicable to Guthion .........................................................................157 
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GUTHION 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about guthion and the effects of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the 

nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term 

federal clean-up activities. Guthion has been found in at least 5 of the 1,699 current or former NPL sites. 

Although the total number of NPL sites evaluated for this substance is not known, the possibility exists 

that the number of sites at which guthion is found may increase in the future as more sites are evaluated. 

This information is important because these sites may be sources of exposure and exposure to guthion 

may be harmful. 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. 

If you are exposed to guthion, many factors will determine whether you will be harmed. These factors 

include the dose (how much), the duration (how long), and how you come in contact with it. You must 

also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and 

state of health. 

1.1 WHAT IS GUTHION? 

Description Guthion is the common name of an organophosphorus insecticide. It is a 

formulation that includes the active ingredient of azinphos-methyl. 

Guthion does not occur naturally in the environment. 

Pure guthion is a colorless to white odorless crystalline solid. Technicalgrade guthion is a cream to yellow-brown granular solid. 

Uses 

 • Pestide uses 

Guthion is used to control pest insects on many crops, especially apples, 

pears, cherries, peaches, almonds, and pistachios. 

Many uses of guthion have been cancelled by the EPA and its few 

remaining uses are being phased out. 
GUTHION 2 

1. PUBLIC HEALTH STATEMENT 

For more information on the physical and chemical properties of guthion, and its production, disposal and 

use, see Chapters 4 and 5. 

1.2 WHAT HAPPENS TO GUTHION WHEN IT ENTERS THE ENVIRONMENT? 

Sources Guthion is primarily released to air from its use as an insecticide. Guthion is 

sprayed on crops primarily using ground-based spray equipment, although it 

can also be sprayed on crops from light-weight planes and helicopters. 

Although a large part of the spray lands directly on the crop, some of the 

smaller droplets that make up the spray can be carried away from the crop by 

the wind to nearby water bodies and soils. 

Guthion residues may also reach nearby rivers, streams, lakes, or ponds by 

water runoff and erosion that occurs during rainfall. 

Manufacturing facilities that produce guthion can also release it to the 

environment during the production process. 

How guthion 

breaks down 

Guthion is not very persistent in the environment. 

Guthion is degraded to many other compounds by microorganisms found in 

soil and water. It is also degraded by sunlight and by reacting with water. 

Guthion does not evaporate very quickly from soil and water. It attaches 

strongly to soil surfaces and does not easily move into groundwater below the 

soil surface. 

For more information on guthion in the environment, see Chapter 6. 
GUTHION 3 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO GUTHION? 

Food—primary 

source of 

exposure 

You are primarily exposed to guthion by ingesting foods treated with this 

pesticide. Apples, pears, peaches, and cherries are crops most likely to 

contain guthion residues, but fewer residues are being found as guthion use 

in agriculture has been diminishing. 

Air You may be exposed to guthion in air in areas close to fruit orchards or other 

crops where guthion is used. 

Workplace People who work in agricultural jobs such as pesticide applicators, fruit 

pickers, and other farm workers can be exposed to higher levels of guthion 

than the average individual, probably by skin contact with the insecticide and 

by inhalation. 

Families of workers can also be exposed because residues on workers’ 

hands, clothes, vehicles, or other personal items can be brought into the 

home. 

Children Children playing on or near areas that have been treated with guthion may 

be exposed to guthion in soil by skin contact, when they accidentally or 

intentionally put soil into their mouths, and through hand-to-mouth activity. 

Children can also be exposed through food and drink. Since children have 

more fruit in their diets, their exposure to guthion may be higher than for 

adults on a body weight basis. 

For more information on human exposure to guthion, see Chapter 6. 

1.4 HOW CAN GUTHION ENTER AND LEAVE MY BODY? 

Enter your body 

• Inhalation 

• Injestion 

• Dermal contact 

If you breathe air containing guthion, you may absorb it into your body 

through the lungs. 

Most guthion in food or water can be absorbed from the digestive tract. 

Guthion may enter your body across the skin. 

Leave your body Once in the body, guthion is rapidly broken down and eliminated from the 

body mainly in the exhaled air, urine, and feces. 

For more information on how guthion enters and leaves the body, see Chapter 3. 
GUTHION 4 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN GUTHION AFFECT MY HEALTH? 

This section looks at studies concerning potential health effects in animal and human studies.

Human exposure Guthion affects the normal function of the nervous system by interfering with 

an important enzyme called acetylcholinesterase. Exposure to guthion can 

result in signs or symptoms of nervous system damage shortly after 

exposure. 

If you experience these symptoms, you should seek medical attention 

immediately. Emergency rooms have drugs that stop the harmful effects of 

guthion. 

Laboratory 

animals 

 

Symptoms observed in animals exposed to high levels of guthion include 

excess saliva, watery eyes, and mustle twitching. 

It is likely that humans exposed to high levels of guthion will have similar 

effects. 

Cancer Guthion has not been shown to cause cancer in people or animals. 

The Department of Health and Human Services (DHHS), the EPA, and the 

International Agency for Research on Cancer (IARC) have not classified the 

carcinogenic potential of guthion in humans. 

Further information on the health effects of guthion in humans and animals can be found in 

Chapters 2 and 3. 

1.6 HOW CAN GUTHION AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Effects in children We do not know whether children are more sensitive than adults to the 

health effects of guthion. The main target for guthion in adults is the 

nervous system, in particular acetylcholinesterase. It is expected that this 

will also be the main target in children. 

Birth defects We do not know if guthion can cause birth defects or other damage to 

developing children. 

Studies in animals have found decreases in fetal growth, nervous system 

damage, and reduced survival, but only at doses that also caused harmful 

health effects in the mothers. 
GUTHION 5 

1. PUBLIC HEALTH STATEMENT 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO GUTHION? 

Wash fruits and 

vegetables 

To reduce the risk of exposure to guthion residue on fresh fruits or 

vegetables, wash the foods prior to eating them. 

If you go to an orchard and pick your own fruit, make sure you wash your 

hands when you are finished since guthion residues can be absorbed 

through the skin. 

Those who live in 

agricultural areas 

If you live near a farm where frequent ground or aerial spraying takes place, 

you may want to remain indoors with your children and pets while the crops 

are being sprayed to lessen your exposure. 

You should discourage your children from entering areas treated with 

guthion. Discourage your children from eating dirt and putting their hands in 

their mouth. Make certain your children wash their hands frequently, 

especially before eating. 

If children play in grass fields or orchards, any pesticides used in these 

areas could collect on clothing. Regular laundering of clothing can reduce 

the potential for this exposure. 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

GUTHION? 

Measuring effects Guthion, like other organophosphorus pesticides, interferes in the human 

body with an enzyme called acetylcholinesterase. Most of the signs and 

symptoms resulting from guthion poisoning are due to this interference with 

acetylcholinesterase. 

A blood test that measures acetylcholinesterase in the red blood cells or a 

similar enzyme in plasma may be useful for detecting exposures to 

potentially harmful levels of guthion. 

Detecting 

exposure 

Because guthion changes to other compounds in the body quickly, it is 

difficult to directly analyze the amount of guthion in a person’s body. Three 

chemicals formed when guthion breaks down can be measured in the urine. 

However, these three compounds are not specific to guthion only, but may 

also indicate exposure to other organophosphorus pesticides. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 
GUTHION 6 

1. PUBLIC HEALTH STATEMENT 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value that is usually based on levels that 

affect animals; they are then adjusted to levels that will help protect humans. Sometimes these not-toexceed levels differ among federal organizations because they used different exposure times (an 8-hour 

workday or a 24-hour day), different animal studies, or other factors. 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. 

Some regulations and recommendations for guthion include the following: 

Food The EPA has set tolerances for residues of guthion in various raw food 

products of 0.2–5 parts of guthion per million parts of food (ppm). 

Workplace air OSHA set a legal limit of 0.2 milligrams per cubic meter (mg/m3

) guthion in 

air averaged over an 8-hour work day. 

NIOSH designated a limit of 10 mg/m3 as a concentration that is 

immediately dangerous to life and health. 

For more information on standards and guidelines for guthion, see Chapter 8. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 
GUTHION 7 

1. PUBLIC HEALTH STATEMENT 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

 Agency for Toxic Substances and Disease Registry 

 Division of Toxicology and Environmental Medicine 

 1600 Clifton Road NE 

 Mailstop F-32 

 Atlanta, GA 30333 

 Fax: 1-770-488-4178 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

 National Technical Information Service (NTIS) 

 5285 Port Royal Road 

 Springfield, VA 22161 

 Phone: 1-800-553-6847 or 1-703-605-6000 

 Web site: http://www.ntis.gov/ 
GUTHION 8 

1. PUBLIC HEALTH STATEMENT 

This page is intentionally blank. 
GUTHION 9 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO GUTHION IN THE UNITED 

STATES 

Guthion, a trade name for azinphos-methyl, is a restricted use organophosphate insecticide that is 

primarily used as a foliar application against phytophagous insect pests on fruit, field, or vegetable crops 

and works as both a contact insecticide and a stomach poison. In 2002, the estimated annual agricultural 

use of guthion had declined to about 1.2 million pounds, nearly a 50% decline from 1997 usage data. The 

total amount of guthion reportedly used in 1997 was 2,091,014 pounds, which was an 18% decrease from 

the amount used (2,548,867 pounds) in 1992. In the Interim Registration Eligibility Decision (interim 

RED) document for guthion, EPA estimated that <2 million pounds are used annually. The greatest 

amounts of guthion have historically been applied to orchard fruits such as apples, pears, cherries, and 

peaches; however, guthion has also been used extensively on cotton, almonds, sugarcane, and several 

other crops. The uses of guthion have been severely restricted in recent years. In 2001, the EPA 

proposed the immediate cancellation of most uses of guthion. Currently, the only crops that guthion can 

still be applied to are: almonds; apples/crabapples; blueberries, lowbush and highbush; Brussels sprouts; 

cherries, sweet and tart; nursery stock (woody shrubs, vines, seeding trees, and nonbearing fruit trees); 

parsley; pears; pistachios; and walnuts. On June 9, 2006, EPA proposed the cancellation of guthion for 

apples, blueberries, cherries, parsley, and pears by 2010 and a phase out of guthion’s other uses by the 

end of 2007. On August 8, 2007, the companies that produce guthion advised the EPA that they intended 

to amend their registrations to terminate certain uses (Brussels sprouts and nursery stock) of guthion by 

September 30, 2007. Uses on walnuts, almonds, and pistachios are scheduled to cease by October 30, 

2009, and all other uses would be terminated by September 30, 2012. 

Guthion is not considered highly persistent in the environment and it degrades through a combination of 

biotic and abiotic mechanisms. Biodegradation occurs readily in soils and water under aerobic conditions 

with half-lives on the order of several days to a few weeks. Background environmental levels of guthion 

are typically below analytical detection limits, and it is rarely detected in areas where it is not being used. 

Elevated levels of guthion are often detected during its application. For example, during the application 

of insecticides to an apple orchard in Massachusetts approximately 1 acre in size by airblast ground 

sprayers, guthion applied at 0.75 kg/ha was detected downwind of the spray zone (75 feet away) at a 

maximum concentration of 3.87 μg/m3

. Within 2 hours, the atmospheric level had dropped to 

0.031 μg/m3

. Guthion has moderate to low mobility in soils based on Koc values in the range of 475– 

3,266. Its leaching potential is considered low and is therefore only occasionally detected in groundwater. 
GUTHION 10 

2. RELEVANCE TO PUBLIC HEALTH 

Guthion was only detected in 4 out of 2,451 groundwater samples collected from 1992 to 1996 in 

20 major hydrological basins across the United States. Guthion is rarely detected in drinking water. In an 

analysis of finished drinking water in 12 states, guthion was detected in 5 out of 225 samples at a mean 

concentration of 0.059 μg/L and a maximum concentration of 0.114 μg/L. Spray drift following aerial 

application, as well as runoff and erosion of treated soils, often leads to contamination of rivers, lakes, 

ponds, and streams adjacent to fields or orchards where guthion has been used as an insecticide. Guthion 

was detected in 64 out of 98 surface water samples (maximum concentration 0.523 μg/L) obtained from 

various sites in a heavy apple growing region along the Yakima River Basin, Washington, during the 

period of May 1999 through January 2000. More recent monitoring data from April to October 

2004 from two sites near the Yakima River had guthion levels ranging from 0.013 to 0.042 μg/L. The 

frequency of detection for guthion at these two sampling locations were approximately 9 and 13%. 

The most important route of exposure to guthion for the general population is through the ingestion of 

foods, especially fruits and vegetables that have been sprayed with this insecticide. Ingestion of 

contaminated drinking water, inhalation exposure, and dermal exposure to guthion are expected to be low 

for the general population. The dietary average daily intake (AVDI) of guthion for eight different age and 

gender groups was estimated from market basket surveys conducted by the FDA from 1986 to 

1991 (more recent surveys are not available). The dietary AVDI of guthion ranges from about 4 to 

31 ng/kg/day (see Table 6-9). Agricultural workers, their family members including children, and 

persons residing near crops that are treated with guthion are expected to be exposed to higher levels than 

the general population. Since guthion is absorbed through the skin, dermal exposure to pesticide 

applicators or workers involved in picking, harvesting, and trimming of crops treated with guthion may be 

high. Although guthion is not considered highly volatile, dust samples in homes of agricultural workers, 

their vehicles, and personal items such as work clothing have been shown to contain detectable levels of 

guthion during the spraying season. This contaminated dust can be resuspended, resulting in dermal and 

inhalation exposures. 

2.2 SUMMARY OF HEALTH EFFECTS 

Available human and animal data suggest that reductions in acetylcholinesterase (AChE) activity are the 

most sensitive end points of guthion toxicity. In both humans and animals, erythrocyte AChE inhibition 

occurs at doses that are several times lower than doses eliciting clinical signs and symptoms. The 

neurotoxicity of guthion is dependent on its bioactivation via a cytochrome P450 mediated desulfuration 

to the oxon form gutoxon. Gutoxon inhibits the enzymatic action of nervous system AChE on the 
GUTHION 11 

2. RELEVANCE TO PUBLIC HEALTH 

neurotransmitter acetylcholine, leading to the accumulation of acetylcholine at the ending of cholinergic 

nerves and resultant continual stimulation of electrical activity. Cholinergic nerves play an important role 

in the normal function of the neuromuscular, central nervous, endocrine, immunological, and respiratory 

systems. In this manner, exposure to guthion may lead to adverse effects on the normal function of many 

important systems. 

There is a paucity of data regarding the inhalation, oral, and dermal toxicity of guthion in humans. 

Limited data are available in studies of the effect of guthion on human erythrocyte AChE and plasma 

cholinesterase (ChE) activities. These studies reported no significant changes in plasma ChE or 

erythrocyte AChE activity in a small group of subjects ingesting 0.057–0.086 mg/kg/day for 4 weeks. 

Nevertheless, there is evidence suggesting that dermal, and perhaps inhalation, exposures of workers to 

guthion may lead to adverse health effects. An increased association was observed between the 

occurrence of systemic illness (defined as an acute illness following pesticide exposure, with symptoms 

and signs not restricted to the eyes or skin) in workers and agricultural use of guthion; however, 

interpretation of this study is complicated by the absence of worker exposure data and the potential 

exposure to other pesticides and formulation components. Although studies of agricultural workers have 

used the detection of urinary metabolites of guthion and ChE activity monitoring to demonstrate exposure 

to guthion, no symptoms or signs of organophosphate poisoning were observed in the exposed workers 

even with documented reductions of 10–20% in erythrocyte AChE activity or whole blood ChE activity. 

These findings are in agreement with animal studies, which indicate that erythrocyte AChE activity is 

very sensitive to guthion and that clinical signs in laboratory animals exposed to guthion are generally 

observed at concentrations that are several times higher than the lowest concentrations eliciting reductions 

in erythrocyte AChE activity. For instance, clinical signs, including hypercholinergy and nicotinic 

effects, salivation, lacrimation, exophthalmus, defecation, urination, and muscle fasciculations, have been 

observed in rats or mice administered single (16–26 mg/kg) or repeated (8 mg/kg/day) lethal oral doses of 

guthion and in rats and mice administered doses ≥3.2 mg/kg/day. However, doses in the range of 0.55– 

3 mg/kg/day in rats and dogs are sufficient to elicit 20–80% reductions in erythrocyte AChE activity with 

reductions >80% being observed at higher doses. Studies with rats and dogs suggest that reductions in 

erythrocyte AChE activity are not related to exposure duration. For instance, 75–92% reductions in 

erythrocyte AChE activity were observed in rats or dogs administered 2–4.3 mg/kg/day guthion on 

gestation days 6–15 or for 13 or 52 weeks and doses of 0.55–1.1 mg/kg/day elicited reductions in the 20– 

47% range in animals dosed for 13 weeks to 2 years. 
GUTHION 12 

2. RELEVANCE TO PUBLIC HEALTH 

Erythrocyte AChE activity appears to be more sensitive than plasma ChE or brain AChE activity to the 

toxic effects of guthion. Biologically significant (≥20%) reductions in erythrocyte AChE activity were 

observed in male and female rats exposed to 4.72 mg/m3

 guthion during 6 hours/day, 5 days/week for up 

to 12 weeks, but brain AChE activity was not affected and plasma ChE activity was reduced by ≥20% 

only in females at one sampling time. Reductions in erythrocyte AChE activity have been observed in 

rats or dogs administered ≥0.55 mg/kg/day, whereas reductions in brain AChE and plasma ChE activity in 

rats and dogs were generally observed at ≥0.96 mg/kg/day. 

Plasma ChE inhibition is used as an indicator of exposure, but does not serve as a reliable indicator of a 

neurotoxic effect. However, inhibition of erythrocyte and brain AChE represents a relevant neurological 

effect. Erythrocyte and/or brain AChE inhibition of 20–59% is considered to represent a less serious 

adverse neurological effect in the absence of more serious indicators of neurotoxicity. In this 

Toxicological Profile, “less serious” effects are those that are not expected to cause significant 

dysfunction or death, or those in which the significance to the organism is not entirely clear. The animal 

studies identified exposure levels at which guthion caused erythrocyte AChE inhibition in the absence of 

more serious indicators of neurotoxicity, which indicates that erythrocyte AChE inhibition at such 

exposure levels may represent the most sensitive effect for guthion toxicity. 

No association was detected between occupational exposure to guthion and the occurrence of congenital 

malformations in a study of male agricultural workers in Spain during 1993 and 1994. Single oral doses 

≥16 mg/kg administered to mice during gestation, elicited reductions in fetal body weight and skeletal 

anomalies. Adverse developmental outcomes such as skeletal abnormalities, decreased pup weight and 

survival, reduced brain weight and ChE activity, and neuromuscular effects were observed in the 

offspring of pregnant rats or mice treated with ≥3.7 mg/kg/day guthion during gestation and gestation and 

lactation. Developmental effects were not evident in rats or mice at oral doses ≤2.5 mg/kg/day. 

Reductions in litter and pup viability were observed in the fetuses of pregnant mice after a single oral 

dose of 20 mg/kg and in the offspring of rats after exposure to 1.3 mg/kg/day during gestation and 

lactation. 

No studies were located regarding the carcinogenic potential of guthion in humans. A 2-year 

carcinogenicity study in rats showed an increased combined incidence of islet cell carcinoma or 

carcinomas of the pancreas in males receiving guthion in the diet for 80 weeks at a concentration resulting 

in an average dose of 10.9 mg/kg/day, followed by a 35-week observation period. However, this lesion 

occurs at a high spontaneous incidence in the animals used in this study and the increased incidence in the 
GUTHION 13 

2. RELEVANCE TO PUBLIC HEALTH 

treated males could not be positively associated with guthion exposure. Similarly, increases in the 

incidence of benign thyroid tumors, malignant thyroid tumors, or combined follicular cell tumors 

observed in male rats exposed to 5.5 or 10.9 mg/kg/day could not be ascribed to treatment with guthion 

due to the high spontaneous incidence of these neoplasms in male rats in this laboratory. There was no 

evidence of the occurrence of treatment-related tumors in female rats in this study or in another study of 

male and female Wistar rats exposed to 0.25–3.11 mg/kg/day for 2 years. Benign and malignant 

neoplasms were observed among dosed and control B6C3F1 mice, but these lesions occur spontaneously 

in mice in this laboratory and the effect could not be positively associated with guthion exposure. The 

incidence of hepatocellular adenomas in male mice administered 5.4–10.7 mg/kg/day groups provide 

equivocal evidence of an association between these lesions and guthion exposure. There were no 

statistically significant associations between tumor incidence and guthion exposure in female mice. The 

results of these studies led the NCI to conclude that, under the conditions of this bioassay, guthion was 

not carcinogenic in male or female B6C3F1 mice or female Osborne-Mendel rats. The incidences of 

neoplasms of the pancreatic islets and of the follicular cells of the thyroid in male rats provide suggestive 

but insufficient evidence of the carcinogenic potential of guthion in male rats. The Department of Health 

and Human Services and the International Agency for Research on Cancer (IARC) have not classified 

guthion as to its carcinogenicity. In 1993, EPA concluded that there was a lack of evidence of 

carcinogenicity of guthion in male and female mice and rats. Currently, the EPA has no carcinogenicity 

classification for guthion. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for guthion. An 

MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 
GUTHION 14 

2. RELEVANCE TO PUBLIC HEALTH 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

• An MRL of 0.02 mg/m3

 has been derived for acute-duration inhalation exposure (14 days or less) 

to guthion. 

Only two studies examining the acute-duration toxicity of inhaled guthion were located. Kimmerle 

(1976) examined a number of end points in rats, but biologically significant alterations were limited to a 

25% reduction in erythrocyte AChE activity in male rats exposed to 4.72 mg/m3

, 6 hours/day, 

5 days/week, for 2 weeks. The reduction in erythrocyte AChE activity in female rats was 18%. No 

adverse effects were observed in male or female rats at exposure concentrations ≤1.24 mg/m3

. EPA 

(1978a) reported a 41% (range 27–59%) reduction in blood ChE activity in rats exposed to guthion 

aerosols (39 mg/m3

) for 1 hour. The results of these studies are strongly supported by several acute- 

(Astroff and Young 1998; Pasquet et al. 1976), intermediate- (Allen et al. 1990; Holzum 1990; Sheets et 

al. 1997), and chronic-duration (Allen et al. 1990; Schmidt and Chevalier 1984) studies in rats and dogs, 

which identified reductions in erythrocyte AChE activity as the most sensitive end point following oral 

exposure to guthion. It is unclear if EPA (1978a) measured reductions in activity of whole blood or 

plasma ChE or erythrocyte AChE. Thus, the erythrocyte AChE inhibition observed in the Kimmerle 

(1976) study was selected as the basis of the acute-duration inhalation MRL. 

In the study by Kimmerle (1976), SPF Wistar rats (10/sex/group) were exposed to aerosolized guthion at 

0.195, 1.24, or 4.72 mg/m3

, 6 hours/day, 5 days/week, for up to 12 weeks. Erythrocyte AChE activity 

measurements were made every 2 weeks after dosing began. Guthion aerosols were generated by first 

dissolving technical-grade guthion in a 1:1 solution of ethanol/polypropylene glycol. Ninety-seven 

percent of the droplets had a diameter of 1±0.5 μm (Kimmerle 1976). The animals were inspected daily 

and weighed weekly. Erythrocyte AChE and plasma ChE activities were determined after 2, 4, 6, 8, 10, 

and 12 weeks. There were no significant changes in appearance or behavior of male or female rats. After 

2 weeks of exposure at 4.72 mg/m3

, erythrocyte AChE activity was reduced by 25 and 18% in males and 

females, respectively. This study identified a no-observed-adverse-effect level (NOAEL) of 1.24 mg/m3 

and a lowest-observed-adverse-effect level (LOAEL) of 4.72 mg/m3

 for reductions in erythrocyte AChE 

activity in male rats. 
GUTHION 15 

2. RELEVANCE TO PUBLIC HEALTH 

A NOAEL/LOAEL approach was used to derive a point of departure to estimate an acute-duration 

inhalation MRL for guthion. The lack of individual animal data or standard errors or standard deviations 

for the mean erythrocyte AChE activity precludes using a benchmark dose analysis approach. The 

NOAEL of 1.24 mg/m3

 was adjusted for intermittent exposure (NOAEL[ADJ]) and a human equivalent 

concentration (NOAEL[HEC]) was calculated using the following equations: 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours = 0.31 mg/m3 

NOAEL[HEC] = NOAEL[ADJ] x RDDRER = 0.31 mg/m3

 x 1.626 = 0.50 mg/m3 

The Regional Deposited Dose Ratio (RDDR) for the extrarespiratory (ER) effects was used to extrapolate 

deposited doses from rats to humans. The RDDR was calculated using EPA software (version 2.3) (EPA 

1994b) with the following parameters: a particle size (mass median aerodynamic diameter, MMAD) of 

0.88 μm with a default geometric standard deviation (sigma g) of 1.0, a default human body weight of 

70 kg and minute volume of 13.8 L, and a rat body weight of 182 g (estimated from the data from 

Kimmerle 1976) and minute volume of 139 mL. 

Based on the information provided by Kimmerle (1976) it was assumed that the sizes of the aerosol 

particles were log-normally distributed in a manner such that 1.5% of these were <0.5 μm and 1.5% were 

>1.5 μm. Based on these assumptions a geometric mean and geometric standard deviation of 0.9 and 

0.23 μm, respectively, were calculated. These values were used to calculate a MMAD of 0.88 μm using 

the recommended equation in Table H-2 of the guidance document Methods for Derivation of Inhalation 

Reference Concentrations and Application of Inhalation Dosimetry (EPA 1994b). 

The NOAEL[HEC] of 0.50 mg/m3

 was divided by an uncertainty factor of 30 (3 for extrapolation from 

animals to humans using dosimetric adjustment and 10 for human variability), resulting in an acuteduration inhalation MRL of 0.02 mg/m3

. 

• An MRL of 0.01 mg/m3

 was derived for intermediate-duration inhalation exposure (15–364 days) 

to guthion. 

Only one study examining the intermediate-duration toxicity of inhaled guthion was located. Kimmerle 

(1976) examined a number of end points in rats, but biologically significant alterations were limited to a 

26–48% reduction in erythrocyte AChE activity in male and female rats exposed to 4.72 mg/m3

, 
GUTHION 16 

2. RELEVANCE TO PUBLIC HEALTH 

6 hours/day, 5 days/week, for up to 12 weeks and a 20% reduction in body weight gain in male rats 

exposed to 4.72 mg/m3

 for 12 weeks; no adverse effects were observed in rats at exposure concentrations 

≤1.24 mg/m3

. Support to the findings of Kimmerle (1976) is provided by several intermediate- (Allen et 

al. 1990; Holzum 1990; Sheets et al. 1997) and chronic-duration (Allen et al. 1990; Schmidt and 

Chevalier 1984) studies in rats and dogs, which identified a reduction in erythrocyte AChE activity as the 

most sensitive end point following oral exposure to guthion. Thus, the erythrocyte AChE inhibition 

observed in the Kimmerle (1976) study was selected as the basis of the intermediate-duration inhalation 

MRL. 

In the study by Kimmerle (1976), SPF Wistar rats (10/sex/group) were exposed to aerosolized guthion at 

0.195, 1.24, or 4.72 mg/m3

, 6 hours/day, 5 days/week, for up to 12 weeks. Erythrocyte AChE activity 

measurements were made every 2 weeks after exposures began. Guthion aerosols were generated by first 

dissolving technical-grade guthion in a 1:1 solution of ethanol/polypropylene glycol. Ninety-seven 

percent of the droplets had a diameter of 1±0.5 μm (Kimmerle 1976). The animals were inspected daily 

and weighed weekly. Erythrocyte AChE and plasma ChE activities were determined after 2, 4, 6, 8, 10, 

and 12 weeks and determinations of hematology, serum glutamic-oxalacetic transaminase (SGOT), serum 

glutamic-pyruvic transaminase (SGPT), alkaline phosphatase (AP), urea, creatinine, and bilirubin were 

conducted after 12 weeks of exposure. At study termination, animals were sacrificed for gross 

examination. The thyroid, thymus, heart, lungs, liver, spleen, kidneys, adrenals, and gonads were 

weighed and examined histologically. Brain AChE activity was also determined. There were no 

significant changes in appearance or behavior of male or female rats. Male rats in the 4.72 mg/m3

 group 

showed a 20% reduction in body weight gain after 12 weeks of exposure. No effects were detected in 

examinations of hemoglobin, erythrocyte counts, thrombocytes, packed cell volume, or leucocyte 

differential counts in male or female rats (Kimmerle 1976). There were also no effects on SGOT, SGPT, 

AP, urea, creatinine, or bilirubin. There were no observed differences in absolute or relative organ 

weights. There were no evident morphological changes or variations in organs or tissues in any of the 

rats. After 4–12 weeks of exposure at 4.72 mg/m3

, erythrocyte AChE activity was reduced by 29–48 and 

26–39% in males and females, respectively. The magnitude of the alterations in erythrocyte AChE 

activity established during the intermediate-duration time points did not appear to be exposure 

duration-related. No biologically significant alterations in erythrocyte AChE activity were observed at 

lower concentrations. The investigators noted that brain AChE activity was not reduced at any of the 

concentrations tested, but the brain AChE activity data were not provided. This study identified a 

NOAEL of 1.24 mg/m3

 and a LOAEL of 4.72 mg/m3 for reductions in erythrocyte AChE activity in male 

rats. 
GUTHION 17 

2. RELEVANCE TO PUBLIC HEALTH 

A NOAEL/LOAEL approach was used to derive a point of departure to estimate an intermediate-duration 

inhalation MRL for guthion. The lack of individual animal data or standard errors or standard deviations 

for the mean erythrocyte AChE activity precludes using a benchmark dose analysis approach. The 

NOAEL of 1.24 mg/m3

 was adjusted for intermittent exposure (NOAEL[ADJ]) and a human equivalent 

concentration (NOAEL[HEC]) was calculated using the following equations: 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours x 5 days/7 days = 0.22 mg/m3 

NOAEL[HEC] = NOAEL[ADJ] x RDDRER = 0.22 mg/m3

 x 1.695 = 0.37 mg/m3 

The RDDR for the extrarespiratory (ER) effects was used to extrapolate deposited doses from rats to 

humans. The RDDR was calculated using EPA software (version 2.3) (EPA 1994b) with the following 

parameters: a particle size MMAD of 0.88 μm with a default geometric standard deviation (sigma g) of 

1.0, a default human body weight of 70 kg and minute volume of 13.8 L, and a rat body weight of 253 g 

(from Kimmerle 1976) and minute volume of 182 mL. 

Based on the information provided by Kimmerle (1976), it was assumed that the sizes of the aerosol 

particles were log-normally distributed in a manner such that 1.5% of these were <0.5 μm and 1.5% were 

>1.5 μm. Based on these assumptions, a geometric mean and geometric standard deviation of 0.9 and 

0.23 μm, respectively, were calculated. These values were used to calculate a MMAD of 0.88 μm using 

the recommended equation in Table H-2 of the guidance document Methods for Derivation of Inhalation 

Reference Concentrations and Application of Inhalation Dosimetry (EPA 1994b). 

The NOAEL[HEC] of 0.37 mg/m3

 was divided by an uncertainty factor of 30 (3 for extrapolation from 

animals to humans using dosimetric adjustment and 10 for human variability), resulting in an 

intermediate-duration inhalation MRL of 0.01 mg/m3

. 

• An MRL of 0.01 mg/m3

 was derived for chronic-duration inhalation exposure (365 days or more) 

to guthion. 

No studies were located that allowed the derivation of a chronic-duration inhalation MRL. However, the 

available acute- and intermediate-duration inhalation studies and the acute-, intermediate-, and chronicduration oral exposure studies support adopting the intermediate-duration MRL for chronic-duration 

exposures. 
GUTHION 18 

2. RELEVANCE TO PUBLIC HEALTH 

Erythrocyte AChE activity was reduced by 29–48% in male rats and 26–39% in female rats exposed to 

guthion aerosols at 4.72 mg/m3

 for 4–12 weeks without evident biologically significant changes in 

activity within the observation period (Kimmerle 1976). Similarly, intermediate- and chronic-duration 

oral exposures to 0.69–0.78 mg/kg/day in dogs (Allen et al. 1990) and 0.75–0.96 mg/kg/day in rats 

(Schmidt and Chevalier 1984) demonstrated biologically significant reductions in erythrocyte AChE 

activity that did not increase in severity with increasing exposure duration for up to 2 years (Allen et al. 

1990; Schmidt and Chevalier 1984). Thus, a chronic-duration inhalation MRL of 0.01 mg/m3

 is adopted 

from the intermediate-duration inhalation MRL and supported by the intermediate- and chronic-duration 

oral exposure studies in dogs and rats, which suggest that there are no duration-dependent increases in the 

severity of the inhibition of erythrocyte AChE activity. 

Oral MRLs 

• An MRL of 0.01 mg/kg/day has been derived for acute-duration oral exposure (14 days or less) to 

guthion. 

Dose-related reductions of 23–82% in erythrocyte AChE activity were observed in rats after single oral 

doses of 2–18 mg/kg guthion (Pasquet et al. 1976) and in female rats following daily oral doses of 

2 mg/kg/day on gestation days 6–15 (Astroff and Young 1998). Dose-related reductions of 21–75% of 

brain AChE activity were observed in rats after single oral doses of 2–18 mg/kg/day (Pasquet et al. 1976). 

Although reductions >20% were observed at the lowest dose 2 hours after exposure, brain AChE activity 

levels had returned to 94–95% of control values after 5 and 24 hours (Pasquet et al. 1976). Brain AChE 

activity was reduced by 27–40% in rats after repeated oral doses of 2 mg/kg/day on gestation days 6– 

15 (Astroff and Young 1998) and by 78% in female rats administered 5.7 mg/kg/day guthion in the feed 

for 1 week (Su et al. 1971). Su et al. (1971) estimated that 4.0 mg/kg/day of guthion were required to 

reduce brain AChE activity by 50%. Clinical signs of neurotoxicity such as lacrimation, salivation, 

defecation, and muscle fasciculatíons were observed in rats and mice receiving lethal oral doses 

≥8 mg/kg/day (EPA 1978a; Short et al. 1980). Developmental effects such as increased incidence of 

supernumerary ribs and malaligned sternebrae, and reduced fetal weight and viability of litters were 

observed in mice or rats at doses ≥5 mg/kg (Kavlock et al. 1985; Pasquet et al. 1976; Short et al. 1980). 

The available data suggest that reduction in erythrocyte AChE activity is the most sensitive end point 

following acute-duration oral exposures to guthion. Although the studies by Astroff and Young (1998) 

and Pasquet et al. (1976) identified a LOAEL of 2 mg/kg/day for significant reductions in erythrocyte 
GUTHION 19 

2. RELEVANCE TO PUBLIC HEALTH 

AChE activity, only the study by Astroff and Young (1998) identified a NOAEL (1 mg/kg/day) and thus, 

it was selected for derivation of the acute-duration oral MRL. 

Pregnant Sprague-Dawley rats were administered guthion (87.7% active ingredient [a.i.]) at 0.5, 1.0, or 

2.0 mg/kg/day by gavage on gestation days 6–15. Erythrocyte AChE was determined on gestation days 

16 and 20 and brain AChE activity was determined on day 20 (Astroff and Young 1998). Inseminated 

females were examined daily for clinical signs. Dam body weight was determined on gestation days 0, 6, 

8, 10, 12, 15, and 20. Food consumption was also determined periodically. Two groups of dams were 

used to establish maternal plasma ChE and erythrocyte and brain AChE activity on gestation days 16 and 

20. Gross pathological examination of dams was conducted. Several reproductive and developmental 

end points, including early or late resorptions, implantation losses, and fetal survival, growth, and 

malformations, were evaluated. The reduction in AChE activity was the most sensitive end point in this 

study. 

A >80% reduction in erythrocyte AChE activity was observed 24 hours after the last 2 mg/kg/day dose. 

A 40% reduction in brain AChE activity was also observed in dams in the 2 mg/kg/day group. Maternal 

plasma ChE activity in the 2.0 mg/kg/day group was approximately 30% lower than in controls on 

gestation day 16, but the effect was not statistically significant. On gestation day 20, maternal brain 

AChE activity remained 27% lower than control values but erythrocyte AChE and plasma ChE activities 

were not significantly different from those in control animals (Astroff and Young 1998). In spite of the 

magnitude of the AChE and ChE activity reductions, no adverse clinical signs were observed in the 

treated dams. There were no reductions in brain or erythrocyte AChE or plasma ChE activities in rats 

administered 0.5 or 1 mg/kg/day (Astroff and Young 1998). 

In order to derive a point of departure to calculate an acute-duration oral MRL, a benchmark dose (BMD) 

approach was applied to the changes in erythrocyte AChE activity observed in female rats exposed to 

guthion by gavage during gestation (Astroff and Young 1998). BMDs and the lower bound of the 95% 

confidence limits of the benchmark doses (BMDLs) were calculated using the EPA Benchmark Dose 

Software (BMDS version 1.3.2; available from EPA). The BMDs and BMDLs are estimates of the doses 

associated with a 20% change in erythrocyte AChE activity. Reductions in erythrocyte AChE activity of 

magnitude <20% are not considered to be biologically significant. The BMD modeling is described in 

greater detail in Appendix A. The BMD and BMDL predicted from the power model are 1.33 and 

1.04 mg/kg/day, respectively. 
GUTHION 20 

2. RELEVANCE TO PUBLIC HEALTH 

An acute-duration oral MRL of 0.01 mg/kg/day was calculated by dividing the BMDL of 1.04 mg/kg/day 

by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human 

variability). 

• An MRL of 0.003 mg/kg/day has been derived for intermediate-duration oral exposure (15– 

364 days) to guthion. 

Dose-related reductions of 37–84% in erythrocyte AChE activity were observed in rats receiving 0.91– 

3.2 mg/kg/day guthion from the feed for 13 weeks (Sheets et al. 1997) and in male and female rats given 

guthion in the feed at 1.3 and 0.55 mg/kg/day, respectively, for 14 weeks and during mating, gestation, 

and parturition (Holzum 1990). Erythrocyte AChE activity was inhibited by 22–40 and 66–88% in male 

dogs receiving 0.69 and 3.8 mg/kg/day, respectively, from the feed for up to 26 weeks and reductions of 

20–43 and 86–92% were observed in female dogs receiving 0.78 and 4.3 mg/kg/day, respectively, for 

26 weeks (Allen et al. 1990). Clinical signs such as tremors, salivation, uncoordinated gait, and diarrhea 

were observed in rats administered guthion in the feed at ≥3.2 mg/kg/day guthion for 13 weeks (Sheets et 

al. 1997), in rats administered 5 mg/kg/day during gestation (Short et al. 1980), or in dogs receiving 

≥0.69 mg/kg/day for 26 weeks (Allen et al. 1990). The available data suggest that reduction in 

erythrocyte AChE activity is the most sensitive end point following intermediate-duration oral exposures 

to guthion. The studies by Allen et al. (1990) and Sheets et al. (1997) identified LOAELs of 0.69– 

0.78 mg/kg/day in dogs and 0.91–1.1 mg/kg/day in rats, respectively, for reductions in erythrocyte AChE 

activity; however, the study by Allen et al. (1990) showed that dogs were more sensitive than rats to the 

anticholinesterase effects of guthion and thus, it was selected for derivation of the intermediate-duration 

oral MRL. 

Technical-grade guthion (91.9% a.i.) was given to beagle dogs (4/sex/group) in the food at concentrations 

of 5.0, 25.0, or 125.0 ppm; these concentrations are equivalent to guthion doses of 0.15, 0.69, and 

3.8 mg/kg/day, respectively, in the males, and 0.16, 0.78, and 4.3 mg/kg/day, respectively, in the females 

(Allen et al. 1990). Dose-related reductions in erythrocyte AChE activity were evident at the week 

4 sampling time. Erythrocyte AChE activity was further reduced from week 4 to 13, but remained 

relatively constant from week 13 to week 26. Statistically nonsignificant reductions in erythrocyte AChE 

activity during the 26-week period were ≤8% in males at 0.15 mg/kg/day and 11–21% in females at 

0.16 mg/kg/day. Reductions in erythrocyte AChE activity were 22–40% in males at 0.69 mg/kg/day and 

20–43% in females at 0.78 mg/kg/day. Reductions in erythrocyte AChE activity from weeks 4 to 26 were 

66–88% in males (3.8 mg/kg/day) and 86–92% in females (4.3 mg/kg/day). Male and female dogs 

receiving guthion doses of 3.8 and 4.3 mg/kg/day, respectively, suffered from an increased incidence of 
GUTHION 21 

2. RELEVANCE TO PUBLIC HEALTH 

mucoid diarrhea and occasional emesis. The same signs, but with a greater severity, were observed in 

male dogs at 0.69 mg/kg/day. These signs were related to treatment with guthion. Terminal body 

weights were reduced by 12 and 16% in male and female dogs of the 3.8 and 4.3 mg/kg/day dose groups, 

respectively, although there was no difference in food consumption among treated and control animals. 

There were no treatment-related hematological effects or changes in urinalysis parameters. Findings were 

negative in hearing and ophthalmoscopic tests on weeks 13 and 26 and there was no treatment-related 

increase in mortality in any dose group (Allen et al. 1990). Clinical chemistry tests showed that albumin 

and albumin/globulin values were significantly reduced in males by 13 and 20%, respectively, in the 

3.8 mg/kg/day group. 

In order to derive a point of departure to calculate an intermediate-duration oral MRL, a BMD approach 

was applied to the changes in erythrocyte AChE activity observed in male and female dogs exposed to 

guthion in the diet for 26 weeks (Allen et al. 1990). BMDs and BMDLs were calculated using the EPA 

Benchmark Dose Software (BMDS version 1.3.2). The BMDs and BMDLs are estimates of the doses 

associated with a 20% change in erythrocyte AChE activity. Reductions in erythrocyte AChE activity of 

magnitude <20% are not considered to be biologically significant. The BMD modeling is described in 

greater detail in Appendix A. A nonhomogeneous variance linear model predicted a BMD and BMDL of 

0.44 and 0.29 mg/kg/day, respectively. 

An intermediate-duration oral MRL of 0.003 mg/kg/day was calculated by dividing the BMDL of 

0.29 mg/kg/day by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for 

human variability). 

• An MRL of 0.003 mg/kg/day has been derived for chronic-duration oral exposure (365 days or 

more) to guthion. 

Dose-related reductions in erythrocyte AChE activity were observed in rats and dogs administered 

guthion in the feed for chronic durations. Statistically significant reductions in erythrocyte AChE activity 

were observed in male and female rats receiving 0.75 and 0.96 mg/kg/day guthion, respectively, from the 

feed for 2 years; however, these were only 10–22% reductions. Biologically significant reductions were 

mainly restricted to doses of 2.33 and 3.11 mg/kg/day in male (20–37% reduction) and female (23–31% 

reduction) rats, respectively (Schmidt and Chevalier 1984). Dogs appeared to be more sensitive to 

guthion. After 1 year, male dogs receiving 0.69 or 3.8 mg/kg/day showed reductions in erythrocyte 

AChE activity of 27 and 86%, respectively, while females receiving 0.78 or 4.3 mg/kg showed reductions 

in erythrocyte AChE activity of 35 and 86%, respectively (Allen et al. 1990). Significant reductions (19– 
GUTHION 22 

2. RELEVANCE TO PUBLIC HEALTH 

67%) in plasma ChE activity were observed in female rats at doses ≥0.96 mg/kg/day and in male rats at 

2.3 mg/kg/day (Schmidt and Chevalier 1984). In male dogs fed guthion for 1 year, reductions in plasma 

ChE activity were 53% at 3.8 mg/kg/day while female dogs showed reductions of 30 and 53% at 0.78 and 

4.3 mg/kg/day, respectively (Allen et al. 1990). Plasma ChE inhibition is used as an indicator of 

exposure, but does not serve as a reliable indicator of a neurotoxic effect. However, inhibition of red 

blood cell AChE and brain AChE represents a relevant neurological effect. Increased relative brain and 

liver weights, lower terminal body weight, and alopecia were observed in rats at 2.3 mg/kg/day (Schmidt 

and Chevalier 1984). Increased incidence of diarrhea and occasional emesis were observed in male dogs 

at 0.69 mg/kg/day. Diarrhea, occasional emesis, and reductions in terminal body weight were also 

observed in male and female dogs receiving guthion at 3.8 and 4.3 mg/kg/day, respectively, from the feed 

for 1 year (Allen et al. 1990). The available chronic-duration data indicate that reduction in erythrocyte 

AChE activity is the most sensitive end point following chronic-duration oral exposures to guthion. The 

52-week study in dogs (Allen et al. 1990) was selected to derive the chronic-duration oral MRL because, 

at similar doses (0.69–0.78 mg/kg/day in dogs after 52 weeks and 0.75–0.96 mg/kg/day in rats after 

2 years), there was a more marked reduction in erythrocyte AChE activity in dogs (20–43%) than in rats 

(10–22%). 

Technical-grade guthion (91.9% a.i.) was administered in the feed at 5, 25, or 125 ppm to beagle dogs 

(4/sex/group) for 52 weeks (Allen et al. 1990). These dietary levels provided guthion doses of 0.15, 0.69, 

and 3.8 mg/kg/day, respectively, to the males, and 0.16, 0.78, 4.3 mg/kg/day, respectively, to the females. 

Erythrocyte AChE and plasma ChE activities were determined prior to treatment and periodically until 

study termination. Dose-related reductions in erythrocyte AChE activity were evident on week 52. A 

statistically nonsignificant reduction of 15% in erythrocyte AChE activity was observed in females at 

0.16 mg/kg/day on week 52, but there was no effect in males. On week 52, reductions in erythrocyte 

AChE activity in males at 0.69 and 3.8 mg/kg/day were 27 and 86%, respectively. Females in the 

0.78 and 4.3 mg/kg/day groups showed 35 and 86% reductions, respectively, in erythrocyte AChE 

activity. Brain AChE activity on week 52 in the 3.8 and 4.3 mg/kg/day groups was reduced by 27 and 

20% in males and females, respectively. Reductions in brain AChE activity were 1 and 10% in female 

and male dogs receiving administered 0.78 and 0.69 mg/kg/day, respectively. No effect on brain AChE 

activity was observed in males administered 0.15 mg/kg/day or females administered 0.16 mg/kg/day. 

Plasma ChE activity was reduced by 53% in males and females administered 3.8 and 4.3 mg/kg/day, 

respectively. No statistically significant reductions in plasma ChE activity were observed in male or 

female dogs administered ≤0.69 or ≤0.78 mg/kg/day, respectively. Terminal body weights were reduced 

by 12% in males in the 3.8 mg/kg/day group and by 16% in females in the 4.3 mg/kg/day group, although 
GUTHION 23 

2. RELEVANCE TO PUBLIC HEALTH 

there was no difference in food consumption among treated and control animals. There were no 

treatment-related hematological effects or changes in urinalysis parameters. Findings were negative in 

hearing and opthalmoscopic tests conducted at study termination and there was no treatment-related 

increase in mortality in any dose group. There were no changes in absolute or relative organ weights in 

females at the doses tested. Absolute and relative spleen weights were reduced in males in a dose-related 

manner with significant reductions in relative spleen weight at doses ≥0.69 mg/kg/day; however, 

congestion of the spleen and increased absolute spleen weight were observed in 4/4 male dogs of the 

control group. A 7–17% decrease in albumin and albumin/globulin values were observed on week 52 in 

males of the 3.8 mg/kg/day group. A 39 and 15% increase in P450 activity was observed in male dogs at 

3.8 mg/kg/day and in female dogs at 4.3 mg/kg/day, respectively. A 34 and 30% increase in 

N-demethylase activity was observed in male dogs at 3.8 mg/kg/day and in female dogs at 4.3 mg/kg/day, 

respectively. Other effects were restricted to the high dose groups (Allen et al. 1990). 

In order to derive a point of departure to calculate a chronic-duration oral MRL, a BMD approach was 

applied to the changes in erythrocyte AChE activity observed in male and female dogs exposed to guthion 

in the diet for 52 weeks (Allen et al. 1990). BMDs and BMDLs were calculated using the EPA 

Benchmark Dose Software (BMDS version 1.3.2). The BMDs and BMDLs are estimates of the doses 

associated with a 20% change in erythrocyte AChE activity. Reductions in erythrocyte AChE activity of 

magnitude <20% are not considered to be biologically significant. The BMD modeling is described in 

greater detail in Appendix A. BMDs of 0.48 and 0.50 mg/kg/day in male and female dogs, respectively, 

and BMDLs of 0.30 and 0.32 mg/kg/day in male and female dogs, respectively, were obtained by analysis 

of the low-dose region of the dose-response curve for dogs exposed to guthion in the diet for 52 weeks. 

The lowest BMDL (0.30 mg/kg/day) was selected as the point of departure. 

A chronic-duration oral MRL of 0.003 mg/kg/day was calculated by dividing the BMDL of 

0.30 mg/kg/day by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for 

human variability). 
GUTHION 24 

2. RELEVANCE TO PUBLIC HEALTH 

This page is intentionally blank. 
GUTHION 25 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of guthion. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 
GUTHION 26 

3. HEALTH EFFECTS 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

The principal toxic effect of guthion in humans and laboratory animals is inhibition of AChE, which 

results in the accumulation of acetylcholine at acetylcholine receptors leading to cholinergic responses in 

the peripheral (muscarinic and nicotinic) and central nervous system and neuromuscular junctions. In this 

Toxicological Profile for Guthion, AChE inhibition of magnitude 20–59% is considered a less serious 

adverse effect in the absence of more serious signs of neurotoxicity. AChE inhibition ≥60% is considered 

a more serious effect independent of the presence or absence of other neurotoxicity indicators. 

3.2.1 Inhalation Exposure 

Guthion has a low volatility; thus, inhalation exposure is likely to be to guthion aerosols rather than 

vapor. It is possible that some of the exposure under these conditions was by the dermal route and/or the 

oral route (grooming). 

3.2.1.1 Death 

No information was located regarding mortality in humans following inhalation exposure to guthion. 

The 1-hour LC50 values and 95% confidence intervals in male and female rats were 69 (62–77) mg/m3 

and 79 (68–93) mg/m3

, respectively (EPA 1978a). There were no mortalities in male or female rats 

exposed to guthion aerosols at concentrations as high as 4.72 mg/m3

 for 6 hours/day, 5 days/week for 

12 weeks (Kimmerle 1976). 
GUTHION 27 

3. HEALTH EFFECTS 

The LC50 values for each species and duration category are shown in Table 3-1 and plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

No information was located regarding systemic effects in humans following inhalation exposure to 

guthion. Available information in animals is restricted to a single report of male and female Wistar rats 

exposed to guthion by inhalation at concentrations as high as 4.72 mg/m3

 for 6 hours/day, 5 days/week for 

12 weeks (Kimmerle 1976). No significant effects on absolute or relative weights of the thyroid, 

adrenals, heart, lungs, liver, or kidneys were observed and there were no indications of exposure-related 

histopathological effects. No significant changes were seen regarding hemoglobin concentration, red 

blood cell concentration, thrombocyte concentration, percent packed cell volume, or leucocyte 

differentials. 

Body Weight Effects. A 19.7% reduction in body weight gain was observed in male, but not female, 

Wistar rats exposed by inhalation to guthion at 4.72 mg/m3

, 6 hours/day, 5 days/week for 12 weeks 

(Kimmerle 1976). Weight gain was not affected at 1.24 mg/m3

. 

The highest NOAEL and all LOAEL values from each reliable study for systemic effects in each species 

and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.3 Immunological and Lymphoreticular Effects 

No information was located regarding immunological or lymphoreticular effects in humans following 

inhalation exposure to guthion. Available information in animals is restricted to a single report of male 

and female Wistar rats exposed to guthion by inhalation at concentrations as high as 4.72 mg/m3

 for 

6 hours/day, 5 days/week for 12 weeks (Kimmerle 1976). No significant effects on absolute or relative 

weights of the thymus or spleen were observed and there were no indications of exposure-related 

histopathological effects. 
19

6979

53

39

82

1.24

4.72

51

1.24

4.72

Table 3-1 Levels of Significant Exposure to Guthion - Inhalation 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

1 hr b 69 M (LC50) 

79 F (LC50) 

EPA 1978a 

Neurological 

2 Rat 

(SpragueDawley) 

1 hr 39 M (41% reduction in blood 

ChE) 

EPA 1978a 

3 Rat 6 hr/d c 1.24 M 4.72 M (25% reduction in Kimmerle 1976 (Wistar) 5 d/wk 2 wk erythrocyte ChE activity) 

INTERMEDIATE EXPOSURE Systemic 

4 Rat 6 hr/d Bd Wt 1.24 M 4.72 M (19.7% reduction in body Kimmerle 1976 (Wistar) 5 d/wk 12 wk weight gain) 
68

4.724.724.724.724.724.72

83

4.72

3

1.24

4.72

Table 3-1 Levels of Significant Exposure to Guthion - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

5 Rat 

(Wistar) 

6 hr/d 5 d/wk 12 wk 

Resp 4.72 Kimmerle 1976 

Cardio 4.72 

Hemato 4.72 Hepatic 4.72 Renal 4.72 

Immuno/ Lymphoret 

6 Rat 

(Wistar) 

6 hr/d 5 d/wk 12 wk 

Endocr 4.72 

4.72 Kimmerle 1976 

Neurological 

7 Rat 

(Wistar) 

6 hr/d 5 d/wk 12 wk 

d

1.24 4.72 (29-48% reduction in 

erythrocyte ChE activity for males; 26-39% for females) 

Kimmerle 1976 

a The number corresponds to entries in Figure 3-1. b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-1. Where such differences exist, only the levels most sensitive gender are presented. c Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.02 mg/m3; the MRL was derived by dividing the NOAEL[HEC] of 0.50 mg/m3 by an unce(3 for extrapolation from animals to humans using dosimetric adjustment and 10 for human variability). d Used to derive an intermediate-duration and chronic-duration inhalation minimal risk level (MRL) of 0.01 mg/m3; the MRL was derived by dividing the NOAEL[HEby an uncertainty factor of 30 (3 for extrapolation from animals to humans using dosimetric adjustment and 10 for human variability). Bd Wt = body weight; Cardio = cardiovascular; ChE = cholinesterase; d = day(s); Endocr = endocrine; F = Female; hemato = hematological; hr = hour(s); Immuno/Limmunological/lymphoreticular; LC50 = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effrespiratory; wk = week(s) 
Death 

Neurological 

GUTHION

Figure 3-1 Levels of Significant Exposure to Guthion - Inhalation

Acute (≤14 days)

ppm 

100 

1r 

2r 

10 

3r 

3r 

1 

0.1 

0.01 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

30
Respiratory 

Cardiovascular Hematological Hepatic Renal Endocrine Body Weight Immuno/Lymphor 

10 

Figure 3-1 Levels of Significant Exposure to Guthion - Inhalation (Continued)

Intermediate (15-364 days) 

Systemic

GUTHION

ppm Neurological 

3. HEALTH EFFECTS

5r 5r 5r 5r 5r 5r 4r 6r 7r 

4r 7r 

1 

0.1 

0.01 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

31
GUTHION 32 

3. HEALTH EFFECTS 

The NOAEL for immunological and/or lymphoreticular effects in Wistar rats for intermediate-duration 

exposure is recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.4 Neurological Effects 

Guthion, an AChE organophosphate, inhibits AChE in the central and peripheral nervous systems. 

Inhibition of AChE results in accumulation of acetylcholine at muscarinic and nicotinic receptors leading 

to peripheral and central nervous system effects. These effects usually appear within a few minutes to 

24 hours after exposure, depending on the extent of exposure. Occupational exposure to guthion via 

inhalation would likely involve oral and dermal exposure routes as well. However, no information was 

located regarding associations between neurological effects in humans and inhalation exposure to guthion 

specifically. 

EPA (1978a) reported a 41% (range 27–59%) reduction in blood plasma cholinesterase (plasma ChE) 

activity in rats exposed to guthion aerosols at 39 mg/m3

 for 1 hour. Erythrocyte AChE activity was 

reduced by >20% (range 25–44%) in male Wistar rats following exposure to guthion aerosols at 

4.72 mg/m3

, 6 hours/day, 5 days/week, for 2–12 weeks; similarly-exposed female Wistar rats exhibited 

26–39% reduced erythrocyte AChE activity after 4–12 weeks of exposure (Kimmerle 1976). The 

reductions in erythrocyte AChE activity were not associated with changes in appearance or behavior of 

the exposed animals. There were no biologically significant changes in erythrocyte AChE activity at 

≤1.24 mg/m3

. The study investigators noted that brain cholinesterase activity was not reduced at any of 

the concentrations tested. 

The highest NOAEL and all LOAEL values from each reliable study for neurological effects in each 

species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.5 Reproductive Effects 

No information was located regarding reproductive effects in humans following inhalation exposure to 

guthion. Available information in animals is restricted to a single report of male and female Wistar rats 

exposed to guthion by inhalation at concentrations as high as 4.72 mg/m3

 for 6 hours/day, 5 days/week for 

12 weeks (Kimmerle 1976). No significant effects on absolute or relative weights of the gonads were 

observed and there were no indications of exposure-related histopathological effects. 
GUTHION 33 

3. HEALTH EFFECTS 

The highest NOAEL and all LOAEL values from each reliable study for reproductive effects in each 

species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.6 Developmental Effects 

No information was located regarding developmental effects in humans or animals following inhalation 

exposure to guthion. 

3.2.1.7 Cancer 

No information was located regarding cancer in humans or animals following inhalation exposure to 

guthion. 

3.2.2 Oral Exposure 

3.2.2.1 Death 

No information was located regarding mortality in humans following oral exposure to guthion. A number 

of studies have examined the acute lethality of guthion in laboratory animals. Single-dose, oral toxicity 

studies with guthion administered to male or female rats reported LD50 values in the range of 11– 

26 mg/kg (DuBois et al. 1957; Gaines 1960; EPA 1978a; Pasquet et al. 1976). These studies suggest that 

male and female rats have similar susceptibilities to the acute lethal toxicity of guthion administered 

orally. 

Single or repeated oral doses of guthion at ≥8 mg/kg/day killed all treated virgin female mice or rats and 

pregnant mice (Kavlock et al. 1985; Short et al. 1980). Elevated mortality rates in the 15–62% range 

were also observed in pregnant rats administered guthion at ≥4.9 mg/kg/day (Holzum 1990; Short et al. 

1980). No significant increases in mortality were observed in male or female mice or rats after acute-, 

intermediate-, or chronic-duration oral exposures to ≤4 mg/kg/day (Allen et al. 1990; Holzum 1990; 

Schmidt and Chevalier 1984; Short et al. 1980). 

No treatment-related increased mortality was observed in male or female rats receiving up to 2.3 or 

3.1 mg guthion/kg/day, respectively, from the diet for up to 2 years (Schmidt and Chevalier 1984) or in 

male and female dogs receiving up to 3.8 or 4.3 mg guthion/kg/day, respectively, from the diet for 

52 weeks (Allen et al. 1990). 
GUTHION 34 

3. HEALTH EFFECTS 

The LD50 values for each species and duration category are shown in Table 3-2 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

No information was located regarding respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, hepatic, renal, dermal, ocular, or metabolic effects in humans. No information was 

located regarding dermal or metabolic effects in animals following oral exposure to guthion. 

Respiratory Effects. Information regarding respiratory effects following oral exposure to guthion is 

limited. There were no gross or histopathological signs of treatment-related respiratory effects in male 

and female Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, respectively, from the 

diet for up to 80 weeks or in male and female B6C3F1 mice receiving up to 10.7 and 21.6 mg 

guthion/kg/day, respectively, from the diet for 80 weeks (NCI 1978). 

Cardiovascular Effects. Information regarding cardiovascular effects following oral exposure to 

guthion is limited. There were no gross or histopathological signs of treatment-related cardiovascular 

effects in male and female Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, 

respectively, from the diet for up to 80 weeks or in male and female B6C3F1 mice receiving up to 

10.7 and 21.6 mg guthion/kg/day, respectively, from the diet for 80 weeks (NCI 1978). 

Gastrointestinal Effects. Treatment-related increased incidences of mucoid feces and diarrhea were 

reported in male dogs receiving 0.69 or 3.8 mg guthion/kg/day or female dogs receiving 4.3 mg 

guthion/kg/day from the diet for up to 1 year (Allen et al. 1990). There were no gross or 

histopathological signs of treatment-related gastrointestinal effects in male and female Osborne-Mendel 

rats receiving up to 10.9 and 9.6 mg guthion/kg/day, respectively, from the diet for up to 80 weeks or in 

male and female B6C3F1 mice receiving up to 10.7 and 21.6 mg guthion/kg/day, respectively, from the 

diet for 80 weeks (NCI 1978). 

Hematological Effects. No biologically significant hematological effects were observed in male or 

female rats receiving up to 2.3 and 3.1 mg guthion/kg/day, respectively, from the diet for up to 2 years; 

significantly elevated thrombocyte counts in high-dose female rats at 6–24 months were found to be 

within the normal range of variability (Schmidt and Chevalier 1984). No treatment-related hematological 
17

1618

25

1311

13

2624

7

8

22

20

8

8

28

2

Table 3-2 Levels of Significant Exposure to Guthion - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

Once (G) 

System 

NOAEL 

(mg/kg) 

Less Serious 

(mg/kg) 

LOAEL 

Serious 

(mg/kg) 

b

16 M (14 day LD50) 18 F (14 day LD50) 

Reference Chemical Form 

EPA 1978a 

2 Rat 

(Sherman) 

Once (GO) 13 M (14 day LD50) b

11 F (14 day LD50) 

Gaines 1960 

3 Rat 

(CD) 

Once (G) 26 M (10 day LD50) b

24 F (10 day LD50) 

Pasquet et al. 1976 

4 Rat 

(CD) 

35 d 1 x/d (GO) 

8 F (100% mortality) Short et al. 1980 

5 Mouse 

(CD-1) 

Once Gd 8 (GO) 

20 F (21/40 maternal death) Kavlock et al. 1985 

6 Mouse 

(CD) 

10 d 1 x/d (GO) 

8 F (100% mortality) Short et al. 1980 

Systemic 

7 Rat 

(SpragueDawley) 

Gd 6-15 (GO) Bd Wt 2 F Astroff and Young 1998 
9

2.5

5

24

16

20

41

5

2

1

2 2

32

16

12

2 18

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Gd 6-15 (GO) Bd Wt 2.5 F 5 F (50% reduction in maternal weight gain) Short et al. 1980 Once Gd 8 (GO) 

Bd Wt 16 F 20 F (19% reduction in 

maternal weight gain) 

Kavlock et al. 1985 

Gd 6-15 (GO) Bd Wt 5 F Short et al. 1980 Gd 6-15 (GO) 

c

1 F 2 F (40% reduction in 

maternal brain ChE activity on gestation day 16) 

2 F (75% reduction in 

maternal erythrocyte ChE activity on gestation day 16) 

Astroff and Young 1998 

Once (G) 16 M (signs of cholinergic poisoning: salivation, 

lacrimation, exophthalmus, defecation, urination, and muscle fasciculations) 

EPA 1978a 

Once (G) 

2 F (21-24% reduction in 

erythrocyte and brain ChE activity) 

18 F (65-82% reduction in 

brain and erythrocyte ChE activity) 

Pasquet et al. 1976 

a 

Key to Species 

Figure (Strain) 

8 Rat 

(CD) 

9 Mouse 

(CD-1) 

10 Mouse 

(CD-1) 

Neurological 

11 Rat 

(SpragueDawley) 

12 Rat 

(SpragueDawley) 

13 Rat 

(CD) 
34

4

8

20

2.8

5.7

35

4

8

36

2.5

5

30

2

40

16

20

1

2

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

35 d 1 x/d (GO) 

4 F 8 F (salivation, urination, 

lacrimation, and tremors) 

Short et al. 1980 

1 wk (F) 2.8 F 5.7 F (78.2% reduction in brain ChE activity) Su et al. 1971 10 d 1 x/d (GO) 

4 F 8 F (salivation, urination, 

lacrimation, and tremors) 

Short et al. 1980 

Gd 6-15 (GO) 2.5 F 5 F (tremors, salivation, and urination observed in 

some pregnant mice) 

Short et al. 1980 

Gd 6-15 (GO) 

2 F Astroff and Young 1998 

Once Gd 8 (GO) 

16 F 20 F (reduced incidence of 

viable litters) 

Kavlock et al. 1985 

Gd 6-15 (GO) 

2 Astroff and Young 1998 

a 

Key to Species 

Figure (Strain) 

14 Rat 

(CD) 

15 Rat 

(Holtzman) 

16 Mouse 

(CD-1) 

17 Mouse 

(CD-1) 

Reproductive 

18 Rat 

(SpragueDawley) 

19 Mouse 

(CD-1) 

Developmental 

20 Rat 

(SpragueDawley) 
23

16

20

29

16

10

2.5

5

64

4.9

27

5

42

11.5

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

21 Mouse 

(CD-1) 

Once Gd 8 (GO) 

16 20 (11% reduction in fetal 

body weight) 

22 Mouse 

(CD-1) 

Once Gd 8 (GO) 

16 (increased incidence of 

supernumerary ribs) 

23 Mouse 

(CD-1) 

Gd 6-15 (GO) 2.5 5 (increased incidence of malaligned sternebrae in 

fetuses) 

INTERMEDIATE EXPOSURE Death 

24 Rat 

(Wistar) 

14 wk before mating to ppd 5 or 28 (F) 

4.9 F 

25 Rat 

(CD) 

Gd 6-ppd 21 (GO) 5 F 

26 Rat 

(Wistar) 

3 wk (F) 11.5 M 

(7/46 rats died or were moribund and sacrificed) (62% mortality in dams) (increased mortality, 

incidence not provided) 

Kavlock et al. 1985 

Kavlock et al. 1985 Short et al. 1980 Holzum 1990 Short et al. 1980 Vos et al. 1983 
85

3.84.3

89

0.75

2.3

31

2.83.2

7.9

43

2.3

11.5

44

2.3

11.5

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

27 Dog 

Cocker spaniel 

26 wk (F) 

b

3.8 M 4.3 F 

Allen et al. 1990 

Systemic 

28 Rat 

(Wistar) 

8 wk (F) Other 0.75 M 2.3 M (15/60 increased incidence of alopecia) Schmidt and Chevalier 

29 Rat 

(Fischer- 344) 

13 wk (F) Bd Wt 

b

2.8 M 3.2 F 

7.9 M (unspecified reduction in 

terminal body weight) 

Sheets et al. 1997 

30 Rat 

(Wistar) 

3 wk (F) Bd Wt 2.3 M 11.5 M (decreased terminal body weight, magnitude not 

provided) 

Vos et al. 1983 

31 Rat 

(Wistar) 

3 wk (F) Endocr 2.3 M 11.5 M (decreased relative pituitary weight; 

unspecified histopathologic findings in the pituitary and adrenals; quantitative results not provided) 

Vos et al. 1983 
86

0.150.78

0.694.3

87

3.84.3

88

3.84.3

21

2.3

11.5

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

32 Dog 

Cocker spaniel 

8 wk (F) Gastro 

b

0.15 M 0.78 F 

b

0.69 M (increased incidence of 

mucoid diarrhea and emesis) 

Allen et al. 1990 

4.3 F (increased incidence of 

mucoid diarrhea and emesis) 

33 Dog 

Cocker spaniel 

26 wk (F) Ocular 

b

3.8 M 4.3 F 

Allen et al. 1990 

34 Dog 

Cocker spaniel 

26 wk (F) Hemato 

b

3.8 M 4.3 F 

Allen et al. 1990 

Immuno/ Lymphoret 

35 Rat 

(Wistar) 

3 wk (F) 2.3 M 11.5 M (decreased relative spleen and mesenteric 

lymph node weights, as well histopathologic findings in the thymus; quantitative results not provided) 

Vos et al. 1983 
63

0.55 1.5

4

0.91 2.8

81

1.1

3.2

37

2.5

5

54

0.15

0.69

3.8

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Neurological 

36 Rat 

(Wistar) 

14 wk before mating to ppd 5 or 28 (F) 

0.55 F (25 and 47% reductions Holzum 1990

in erythrocyte ChE activity on lactation days 5 and 28, respectively) 

1.5 F (75 and 84% reductions 

in erythrocyte ChE activity on lactation days 5 and 28, respectively) 

37 Rat 

(Fischer- 344) 

13 wk (F) 0.91 M (37% reduction in Sheets et al. 1997 erythrocyte ChE activity 

on week 13) 

2.8 M (84% reduction in 

erythrocyte ChE activity on week 13) 

38 Rat 

(Fischer- 344) 

13 wk (F) 

1.1 F 3.2 F (tremors, incoordinated Sheets et al. 1997

gait, and perianal staining) 

39 Rat 

(CD) 

Gd 6-ppd 21 (GO) 2.5 F 5 F (tremors, salivation, and Short et al. 1980 urination were observed 

in some pregnant CD rats) 

40 Dog 

Cocker spaniel 

26 wk (F) 

Allen et al. 1990 d 0.15 M 0.69 M (22-40% reduction in 

erythrocyte ChE activity) 

3.8 M (66-88% reduction in 

erythrocyte ChE activity; 37-58% reduction in plasma ChE activity; 27% reduction in brain ChE) 
95

3.74.9

45

2.3

11.5

66

0.430.55

1.31.5

67

1.5

4.9

90

3.8

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

14 wk before mating to ppd 5 or 28 (F) 

b

3.7 M 4.9 F 

Holzum 1990 

3 wk (F) 2.3 M 11.5 M (unspecified histopathologic findings 

in the testes) 

Vos et al. 1983 

14 wk before mating to ppd 5 or 28 (F) 

b

0.43 M 0.55 F 

b

1.3 M (statistically significant 

reduction in viability of pups on ppd 5) 

1.5 F (statistically significant 

reduction in viability of pups on ppd 5) 

Holzum 1990 

14 wk before mating to ppd 5 or 28 (F) 

1.5 F 4.9 F (significantly lower 

(19-25%) pup weight, relative to controls, on ppd 14 and 21) 

Holzum 1990 

14 wk before mating to ppd 5 or 28 (F) 

3.8 M Holzum 1990 

a 

Key to Species 

Figure (Strain) 

Reproductive 

41 Rat 

(Wistar) 

42 Rat 

(Wistar) 

Developmental 

43 Rat 

(Wistar) 

44 Rat 

(Wistar) 

45 Rat 

(Wistar) 
91

1.5

4.9

11

2.5

5

92

2.5

5

71

2.33.1

56

0.753.11

2.33

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

46 Rat 

(Wistar) 

14 wk before mating to ppd 5 or 28 (F) 

1.5 F 4.9 F (in pups: significant 

(19%) reduction in brain weight on ppd 5 and 46% reduction in brain ChE activity on ppd 28) 

Holzum 1990 

47 Rat 

(CD) 

Gd 6-ppd 21 (GO) 2.5 5 (34% reduction in pup weight; 85% reduction in 

pup survival) 

Short et al. 1980 

48 Rat 

(CD) 

Gd 6-ppd 21 (GO) 2.5 5 (in pups in the surviving litter: rear legs were stiff, 

at right angles to the body; pups lacked neuromuscular coordination of hind legs; muscle tremors in the tail and upturned snouts) 

Short et al. 1980 

CHRONIC EXPOSURE Death 

49 Rat 

(Wistar) 

2 yr (F) 

b

2.3 M 3.1 F 

Schmidt and Chevalier 

Systemic 

50 Rat 

(Wistar) 

2 yr (F) Bd Wt 

b

0.75 M 3.11 F 

2.33 M (10% reduction in body 

weight) 

Schmidt and Chevalier 
69

0.75

2.3

70

2.33.1

72

2.30.96

3.1

73

2.30.96

93

2.33.1

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

2 yr (F) Dermal 0.75 M 2.3 M (15/60 increased incidence of alopecia) Schmidt and Chevalier 2 yr (F) Ocular 

b

2.3 M 3.1 F 

Schmidt and Chevalier 

2 yr (F) Hemato 2.3 M b

0.96 F 

3.1 F (thrombocyte values 

significantly elevated by 20-25%) 

Schmidt and Chevalier 

2 yr (F) Hepatic 2.3 M b

0.96 F 

Schmidt and Chevalier 

2 yr (F) Renal 

b

2.3 M 3.1 F 

Schmidt and Chevalier 

a 

Key to Species 

Figure (Strain) 

51 Rat 

(Wistar) 

52 Rat 

(Wistar) 

53 Rat 

(Wistar) 

54 Rat 

(Wistar) 

55 Rat 

(Wistar) 
75

0.150.78

0.694.3

76

3.84.3

77

3.84.3

78

0.690.78

79

0.69

3.8

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

52 wk (F) Gastro 

b

0.15 M 0.78 F 

b

0.69 M (increased incidence of 

mucoid diarrhea and emesis) 

Allen et al. 1990 

4.3 F (increased incidence of 

mucoid diarrhea and emesis) 

52 wk (F) Ocular 

b

3.8 M 4.3 F 

Allen et al. 1990 

52 wk (F) Hemato 

b

3.8 M 4.3 F 

Allen et al. 1990 

52 wk (F) Hepatic 

b

0.69 M 0.78 F 

Allen et al. 1990 

52 wk (F) Bd Wt 0.69 M 3.8 M (12% decrease in terminal body weight) Allen et al. 1990 

a 

Key to Species 

Figure (Strain) 

56 Dog 

Cocker spaniel 

57 58 59 60 

Dog Cocker spaniel Dog Cocker spaniel Dog Cocker spaniel Dog Cocker spaniel 
94

3.84.3

57

0.25

2.30.75

84

0.15

0.69 3.8

Table 3-2 Levels of Significant Exposure to Guthion - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

52 wk (F) Renal 

b

3.8 M 4.3 F 

Allen et al. 1990 

2 yr (F) 0.25 M 2.3 M (38-49% reduction in plasma ChE activity; 32% 

reduction in brain ChE activity; 7-11% increase in relative brain weight) 

Schmidt and Chevalier 

0.75 M (10-22% reduction in 

erythrocyte ChE activity) 

52 wk (F) 

e

0.15 M 0.69 M (27% reduction in 

erythrocyte ChE activity) 

3.8 M (86% reduction in 

erythrocyte ChE activity) 

Allen et al. 1990 

a 

Key to Species 

Figure (Strain) 

61 Dog 

Cocker spaniel 

Neurological 

62 Rat 

(Wistar) 

63 Dog 

Cocker spaniel 

a The number corresponds to entries in Figure 3-2. b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-2. Where such differences exist, only the levels most sensitive gender are presented. c Used to derive an acute-duration oral minimal risk level (MRL) of 0.01 mg/kg/day; the MRLs were derived by dividing the BMDL of 1.04 mg/kg/day by an uncertain(10 for animal to human extrapolation and 10 to protect sensitive subpopulations). d Used to derive an intermediate-duration oral minimal risk level (MRL) of 0.003 mg/kg/day; the MRL was derived by dividing the BMDL of 0.29 mg/kg/day by an un100 (10 for animal to human extrapolation and 10 to protect sensitive subpopulations). e Used to derive a chronic-duration oral minimal risk level (MRL) of 0.003 mg/kg/day; the MRL was derived by dividing the BMDL of 0.30 mg/kg/day by an uncertain(10 for animal to human extrapolation and 10 to protect sensitive subpopulations). ChE = cholinesterase; Bd Wt = body weight; d = day(s); (F) = feed; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = gestational day; (GO) = gavage in oilhematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; ppd = post-parttime(s); wk = week(s); yr = year(s) 
Death 

Body Weight Neurological Reproductive Developmental 

GUTHION

Figure 3-2 Levels of Significant Exposure to Guthion - Oral 

Acute (≤14 days) 

Systemic 

mg/kg/day 

100 

3r 

5m 9m 19m 21m 13r 1r 9m 12r 19m 21m 22m 

2r 10 

6m 4r 16m 14r 

15r 10m 8r 17m 23m 

16m 14r 

15r 8r 17m 23m 

7r 11r 11r 13r 18r 20r 

1 11r 

0.1 

0.01 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

47
Death 

Gastrointestinal Hematological Endocrine Ocular Body Other 

Weight 

Figure 3-2 Levels of Significant Exposure to Azinphos-methyl - Oral (Continued)

Intermediate (15-364 days)

Systemic 

GUTHION

mg/kg/day 

100 

26r 31r 30r 10 

29r 

24r 25r

27d 34d 33d 

29r

31r 30r 28r 

1 

28r 32d 

32d 

0.1 

0.01 

0.001 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

48
Immuno/Lymphor 

Neurological Reproductive Developmental 

Figure 3-2 Levels of Significant Exposure to Guthion - Oral (Continued)

Intermediate (15-364 days)

GUTHION

mg/kg/day 

100 

35r 42r 10 

39r 47r 48r 

40d 

44r 46r 

41r 45r 38r 37r 39r 47r 48r 35r 42r 

36r 44r 46r 43r 38r 1 37r

40d

36r

43r 

40d 

0.1 

0.01 

0.001 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

49
Death 

Gastrointestinal Hematological Hepatic Renal Dermal Ocular Body Neurological 

Weight 

Figure 3-2 Levels of Significant Exposure to Guthion - Oral (Continued)

Chronic (≥365 days)

Systemic 

GUTHION

mg/kg/day 

10 

58d 61d 57d 60d 63d 

53r 

49r 55r 51r 52r 50r 62r 

1 53r 54r 

51r 50r 62r 56d 59d 60d 63d 

62r 

56d 63d 

0.1 

0.01 

0.001 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

50
GUTHION 51 

3. HEALTH EFFECTS 

effects were observed in male or female dogs receiving as much as 3.8 or 4.3 mg guthion/kg/day, 

respectively, from the diet for up to 12 months (Allen et al. 1990). 

Musculoskeletal Effects. Information regarding musculoskeletal effects following oral exposure to 

guthion is limited. There were no gross or histopathological signs of treatment-related musculoskeletal 

effects in male and female Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, 

respectively, from the diet for up to 80 weeks or in male and female B6C3F1 mice receiving up to 

10.7 and 21.6 mg guthion/kg/day, respectively, from the diet for 80 weeks (NCI 1978). 

Hepatic Effects. Information regarding hepatic effects following oral exposure to guthion is limited. 

There were no gross or histopathological signs of treatment-related hepatic effects in male and female 

Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, respectively, from the diet for up to 

80 weeks or in male and female B6C3F1 mice receiving up to 10.7 and 21.6 mg guthion/kg/day, 

respectively, from the diet for 80 weeks (NCI 1978). 

Renal Effects. Urinalysis did not reveal evidence of exposure-related renal effects in male or female 

rats receiving 2.3 or 3.1 mg guthion/kg/day, respectively, from the diet for up to 2 years (Schmidt and 

Chevalier 1984) or in male and female dogs receiving 3.8 or 4.3 mg guthion/kg/day, respectively, from 

the diet for 52 weeks (Allen et al. 1990). Pathologic examinations of the guthion-exposed rats and dogs 

revealed no signs of treatment-related adverse renal effects (Allen et al. 1990; Schmidt and Chevalier 

1984). There were no gross or histopathological signs of treatment-related renal effects in male and 

female Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, respectively, from the diet 

for up to 80 weeks or in male and female B6C3F1 mice receiving up to 10.7 and 21.6 mg guthion/kg/day, 

respectively, from the diet for 80 weeks (NCI 1978). 

Endocrine Effects. Vos et al. (1983) reported decreased relative pituitary weight as well as 

unspecified histopathologic findings in the pituitary and adrenals of male Wistar rats receiving 

11.5 mg/kg/day guthion from the diet for 3 weeks. This effect was not seen in rats receiving 

2.3 mg/kg/day. There were no histopathological indications of treatment-related effects on thyroid, 

parathyroid, pituitary, or adrenal tissues among male and female rats receiving up to 2.3 or 3.1 mg 

guthion/kg/day, respectively, from the diet for up to 2 years (Schmidt and Chevalier 1984), male and 

female dogs receiving up to 3.8 or 4.3 mg guthion/kg/day, respectively, from the diet for 52 weeks (Allen 

et al. 1990), male and female Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, 
GUTHION 52 

3. HEALTH EFFECTS 

respectively, from the diet for up to 80 weeks (NCI 1978), or male and female B6C3F1 mice receiving up 

to 10.7 and 21.6 mg guthion/kg/day, respectively, from the diet for 80 weeks (NCI 1978). 

Ocular Effects. No treatment-related ocular effects were observed in male or female rats receiving up 

to 2.3 or 3.1 mg guthion/kg/day, respectively, from the diet for up to 2 years (Schmidt and Chevalier 

1984). No treatment-related effects were observed in opthalmoscopic examinations conducted in male 

and female dogs receiving up to 3.8 or 4.3 mg guthion/kg/day, respectively, from the diet for 52 weeks 

(Allen et al. 1990). 

Body Weight Effects. Reductions in body weight gain or terminal body weights have been observed 

following acute, intermediate, and chronic oral exposure to guthion. A 19% decrease in maternal body 

weight gain was observed in mouse dams administered a single gavage dose of 20 mg guthion/kg/day on 

gestational day 8 (Kavlock et al. 1985). A 50% reduction in maternal body weight gain was observed in 

rat dams administered 5 mg guthion/kg/day by gavage on gestational days 6–15; the 5 mg/kg/day dose 

level also resulted in 25% decreased food consumption and clinical signs of AChE inhibition (tremors and 

salivation) (Short et al. 1980). Maternal body weight was not adversely affected in other rats or mice 

administered 2 or 2.5 mg guthion/kg/day, respectively, by gavage on gestational days 6–15 (Astroff and 

Young 1998; Short et al. 1980). Male and female dogs receiving 3.8 and 4.3 mg guthion/kg/day, 

respectively, from the diet for 52 weeks exhibited 12 and 16% lower mean final body weights than their 

respective controls in the absence of a treatment-related effect on food consumption; no significant body 

weight effects were seen in the male or female dogs receiving doses ≤0.69 and 0.78 mg/kg/day, 

respectively (Allen et al. 1990). Body weights of male rats receiving 2.3 mg guthion/kg/day from the diet 

were approximately 10% lower than controls throughout 2 years of treatment in the absence of a 

treatment-related effect on food consumption; no significant treatment-related effects on body weight 

were seen at lower doses in males or in females receiving up to 3.1 mg guthion/kg/day (Schmidt and 

Chevalier 1984). Significantly decreased growth (approximately 10–15% lower than controls) was 

observed consistently during 80 weeks of dietary exposure of Osborne-Mendel rats receiving 5.5 or 

10.9 mg guthion/kg/day (males) and 9.6 mg/kg/day (females) (NCI 1978). There were no indications of 

treatment-related body weight effects in similarly-exposed male and female B6C3F1 mice receiving up to 

10.7 and 21.6 mg guthion/kg/day, respectively (NCI 1978). An unspecified decrease in body weight 

(investigators noted that most body weight changes observed in this study of several compounds were 5– 

15%) was observed in male rats following 13 weeks of exposure to 7.9 mg/kg/day, but not after exposure 

to 2.8 mg/kg/day (Sheets et al. 1997); decreases in body weight and food consumption were observed in 

females at 7 mg/kg/day but not at 3.2 mg/kg/day. 
GUTHION 53 

3. HEALTH EFFECTS 

Other Systemic Effects. Among male and female rats receiving 2.3 and 3.1 mg guthion/kg/day, 

respectively, from the diet for up to 2 years, chronic alopecia was noted. Clinical chemistry performed on 

these rats did not reveal signs of treatment-related effects (Schmidt and Chevalier 1984). Serum albumin 

and albumin/globulin values were significantly reduced in male dogs receiving 3.8 mg guthion/kg/day 

from the diet for 52 weeks; the magnitudes of these reductions in albumin and albumin/globulin ranged 

from 7 to 13% and from 17 to 20%, respectively, from weeks 13 to 52 (Allen et al. 1990). Dietary 

administration of guthion to male and female dogs for 52 weeks at concentrations resulting in doses of 

3.8 mg/kg/day (males) and 4.3 mg/kg/day (females) resulted in 39 and 15% increased cytochrome 

P-450 activity (males and females, respectively) (Allen et al. 1990). 

The highest NOAEL value and all LOAEL values for systemic effects in each reliable study for each 

species and duration category are shown in Table 3-2 and plotted in Figure 3-2. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No information was located regarding immunological or lymphoreticular effects in humans following oral 

exposure to guthion. Vos et al. (1983) reported decreased relative spleen and mesenteric lymph node 

weights, as well as unspecified histopathologic findings in the thymus in male Wistar rats receiving 

11.5 mg guthion/kg/day from the diet for 3 weeks; no effects were seen at a dose level of 2.3 mg/kg/day. 

No evidence of treatment-related histopathological effects were seen in sections of spleens from male and 

female rats receiving up to 2.3 and 3.1 mg guthion/kg/day, respectively, from the diet for up to 2 years 

(Schmidt and Chevalier 1984). Significantly lower mean relative spleen weights (0.29 and 0.26% of body 

weight, compared to 0.63% in controls) were noted in male dogs receiving 0.69 and 3.8 mg 

guthion/kg/day from the diet for 52 weeks (Allen et al. 1990). However, the study authors considered this 

effect to have been the result of an unusually high incidence of congested spleen in the control dogs rather 

than a treatment-related effect. No significant treatment-related effect on spleen weight was seen in 

similarly-exposed female dogs at doses as high as 4.3 mg/kg/day (Allen et al. 1990). There were no gross 

or histopathological signs of treatment-related immunological or lymphoreticular effects in spleen and 

lymph nodes of male and female Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, 

respectively, from the diet for up to 80 weeks or in male and female B6C3F1 mice receiving up to 10.7 

and 21.6 mg guthion/kg/day, respectively, from the diet for 80 weeks (NCI 1978). 
GUTHION 54 

3. HEALTH EFFECTS 

3.2.2.4 Neurological Effects 

Available human data are limited to observations of the lack of significant changes in plasma ChE or 

erythrocyte AChE activity in a group of five subjects receiving guthion orally at up to 0.29 mg/kg/day for 

4 weeks (Rider and Puletti 1969; Rider et al. 1970, 1971, 1972). 

As discussed in detail in Section 3.5. Mechanisms of Action, guthion poisoning is characterized by the 

inhibition of AChE in the central and peripheral nervous system. AChE is also present in erythrocytes. 

In in vitro assays, roughly equivalent inhibition of AChE in erythrocytes and neural tissues is produced by 

a given concentration of organophosphates such as guthion (Iyaniwura 1991). Therefore, inhibition of 

erythrocyte AChE can be used as a surrogate indicator of the extent of inhibition of neural AChE. Blood 

plasma also contains other cholinesterases (ChEs). In humans, plasma ChE is almost exclusively 

composed of butyrylcholinesterase, which is capable of hydrolyzing acetylcholine and butyrylcholine in 

vitro. The in vivo substrate of plasma ChE is unknown. In general, plasma ChE can be inhibited by 

guthion at lower levels of exposure than those required to inhibit neural or erythrocyte AChE. Plasma 

ChE activity is considered to be a sensitive indicator of exposure to organophosphates such as guthion, 

but not an indicator of a neurologic effect. 

The most commonly observed neurological effects in laboratory animals treated orally with guthion are 

the inhibition of erythrocyte AChE activity and clinical signs of cholinesterase inhibition (Allen et al. 

1990; Astroff and Young 1998; Holzum 1990; Pasquet et al. 1976; Schmidt and Chevalier 1984; Sheets et 

al. 1997; Short et al. 1980; Su et al. 1971). Treatment-related decreased erythrocyte AChE activity is 

generally the most sensitive end point. Reductions in brain AChE activity are observed at somewhat 

higher doses than those affecting erythrocyte AChE. Clinical signs are only evident in animals at doses 

several times higher than those eliciting reductions in AChE activity. Cholinergic signs such as 

salivation, lacrimation, exophthalmus, defecation, urination, and muscle fasciculations have been 

observed in rats and mice administered lethal oral doses of guthion (EPA 1978a; Pasquet et al. 1976; 

Short et al. 1980) and in rats and mice administered guthion doses ≥3.2 mg/kg/day (Sheets et al. 1997; 

Short et al. 1980). Reductions in erythrocyte AChE activity of ≥75% (considered a serious adverse 

effect) were observed in rats and dogs after acute, intermediate, or chronic oral exposures to guthion at 

doses ≥2 mg/kg/day (Allen et al. 1990; Astroff and Young 1998; Pasquet et al. 1976; Sheets et al. 1997) 

and reductions in the range of 20–50% have been observed in rats or dogs after acute-to-chronic oral 

exposure to guthion at doses ranging from 0.55 to 2 mg/kg/day (Allen et al. 1990; Holzum 1990; Pasquet 

et al. 1976; Schmidt and Chevalier 1984; Sheets et al. 1997). No biologically significant changes in 
GUTHION 55 

3. HEALTH EFFECTS 

erythrocyte AChE activity were seen in rats receiving 0.43 mg guthion/kg/day for at least 14 weeks 

(Holzum 1990), dogs receiving 0.15–0.16 mg guthion/kg/day for 52 weeks (Allen et al. 1990), or rats 

receiving 0.25–0.31 mg guthion/kg/day for 2 years (Schmidt and Chevalier 1984). 

Brain AChE activity was reduced by 20–78% in rats and dogs receiving acute or chronic oral doses of 

guthion ranging from 0.96 to 5.7 mg/kg/day; lower oral doses failed to elicit levels of biologically 

significant (≥20%) brain AChE inhibition (Allen et al. 1990; Astroff and Young 1998; Pasquet et al. 

1976; Schmidt and Chevalier 1984; Su et al. 1971). 

Reductions of 35–58% in plasma ChE activity were observed in rats and dogs receiving at 0.96–4.3 mg 

guthion/kg/day orally for up to 2 years and 52 weeks, respectively (Allen et al. 1990; Schmidt and 

Chevalier 1984). However, guthion-induced reductions in plasma ChE activity are of questionable 

biological significance. 

No effect on hearing was evident in male or female dogs receiving up to 3.8 and 4.3 mg guthion/kg/day, 

respectively, from the diet for up to 52 weeks (Allen et al. 1990). 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and 

duration category are presented in Table 3-2 and plotted in Figure 3-2. 

Neurological effects associated with perinatal exposure are presented in Section 3.2.2.6 (Developmental 

Effects). 

3.2.2.5 Reproductive Effects 

No information was located regarding reproductive effects in humans following oral exposure to guthion. 

Unspecified histopathologic findings were observed in the testes of Wistar rats receiving 11.5 mg 

guthion/kg/day from the diet for 3 weeks; no indications of treatment-related reproductive effects were 

seen at a dose level of 2.3 mg/kg/day (Vos et al. 1983). No treatment-related effects on insemination, 

fertility, or gestation indices were seen in male and female rats receiving guthion from the diet for 

14 weeks before mating and throughout mating, gestation, and lactation at doses ranging from 0.43 to 

4.9 mg/kg/day (Holzum 1990). There were no indications of treatment-related effects on reproductive 

organ weights or pathology among male and female rats receiving up to 2.3 or 3.1 mg guthion/kg/day, 
GUTHION 56 

3. HEALTH EFFECTS 

respectively, from the diet for up to 2 years (Schmidt and Chevalier 1984) or in male and female dogs 

receiving up to 3.8 or 4.3 mg guthion/kg/day, respectively, from the diet for 52 weeks (Allen et al. 1990). 

There were no gross or histopathological signs of treatment-related effects on reproductive tissues of male 

and female Osborne-Mendel rats receiving up to 10.9 and 9.6 mg guthion/kg/day, respectively, from the 

diet for up to 80 weeks or male and female B6C3F1 mice receiving up to 10.7 and 21.6 mg 

guthion/kg/day, respectively, from the diet for 80 weeks (NCI 1978). 

3.2.2.6 Developmental Effects 

No information was located regarding developmental effects in humans following oral exposure to 

guthion. 

Neurological effects were observed in offspring from pregnant rats administered guthion at 5 mg/kg/day 

from gestation day 6 to postparturition day 21 by gavage (Short et al. 1980). One day after weaning, pups 

in the surviving litter presented stiff rear legs at right angles to the body and lack of neuromuscular 

coordination in the use of the hind legs, as well as muscle tremors in the tail and upturned snouts (Short et 

al. 1980). These effects were not observed at 2.5 mg/kg/day. Fetal brain cholinesterase activity on 

gestation day 20 was unaffected in pups from Sprague-Dawley rats administered guthion at 2 mg/kg/day 

on gestation days 6–15 (Astroff and Young 1998). 

A marked increase in the incidence of supernumerary ribs was observed in the offspring of pregnant mice 

administered 16 or 20 mg guthion/kg by gavage on gestation day 8; the 20 mg/kg dose level was also fatal 

to 21 of 40 treated dams (Kavlock et al. 1985). The incidence of supernumerary ribs was 3% in the 

control group, and approximately 24 and 58% in the 16 and 20 mg/kg groups, respectively; however, the 

authors reported an inverse correlation between maternal weight gain and the incidence of supernumerary 

ribs and suggested that there was an association between nonspecific adverse health effects in the dams 

and the development of supernumerary ribs in fetuses. 

An 11% reduction in fetal weight was observed at gestation day 18 in the offspring of pregnant mice 

administered 20 mg guthion/kg by gavage on gestation day 8; this dose level was also associated with 

53% maternal mortality (21/40 dams) (Kavlock et al. 1985). An apparently maternally-nontoxic gavage 

dose of 16 mg guthion/kg/day did not affect fetal weight. Significantly reduced pup weight (34% lower 

than controls) and perinatal survival (85% lower than controls) were noted in the offspring of rat dams 

administered 5 mg guthion/kg/day by gavage on gestation day 6 through postpartum day 21 (Short et al. 
GUTHION 57 

3. HEALTH EFFECTS 

1980). However, this dosing regimen also resulted in 62% maternal death, depressed maternal body 

weight gain, and neurological signs of cholinesterase inhibition. There were no significant maternal or 

fetal effects at dose levels ≤2.5 mg/kg/day. No effects on fetal body weights were seen following 

administration of 2.0 mg guthion/kg/day to pregnant rats on gestation days 6–15 (Astroff and Young 

1998), or 5.0 mg/guthion/kg/day to pregnant rats or mice on gestation days 6–15 (Short et al. 1980). 

Significantly decreased survival was observed in the 5-day-old offspring of male and female rats 

administered 1.3 and 1.5 mg guthion/kg/day in the diet for 14 weeks prior to mating and throughout 

mating, gestation, and postparturition day 5 (Holzum 1990). These doses were associated with 69 and 

75% reductions in erythrocyte AChE in the parental rats (Holzum 1990). 

Guthion exposure did not elicit external, visceral, or skeletal malformations or variations in offspring of 

rats administered guthion at 2.0 mg/kg/day on gestation days 6–15 (Astroff and Young 1998) or skeletal 

anomalies in pups from mice administered guthion at 2.5 mg/kg/day on gestation days 6–15 (Short et al. 

1980); however, pups of the 5 mg/kg/day dose group exhibited increased incidence of malaligned 

sternbrae (Short et al. 1980). 

3.2.2.7 Cancer 

No studies were located regarding cancer in humans following oral exposure to guthion. 

The carcinogenicity of guthion was assessed in groups of male and female rats and mice orally exposed 

for a lifetime (NCI 1978; Schmidt and Chevalier 1984). No treatment-related effects on incidence of 

histopathologic neoplastic lesions were seen in male or female Wistar rats exposed to guthion doses as 

high as 3.11 mg/kg/day in the diet for 2 years (Schmidt and Chevalier 1984). The NCI (1978) reported 

significant increases in incidences of benign thyroid tumors, malignant thyroid tumors, or combined 

follicular cell tumors in male Osborne-Mendel rats receiving estimated doses of 5.5 or 10.9 mg 

guthion/kg/day from the diet for 80 weeks followed by a 35-week observation period and significant 

increases in the combined incidence of islet cell carcinoma or carcinomas in the pancreas of the 

10.9 mg/kg/day male rats. However, it was noted that these tumor incidences could not be clearly 

attributed to treatment with guthion due to high spontaneous incidences of these tumors in male OsborneMendel rats at the laboratory where the study was performed. There was no evidence of treatment-related 

increased tumors in the guthion-treated female rats receiving estimated oral doses as high as 

9.6 mg/kg/day (NCI 1978). 
GUTHION 58 

3. HEALTH EFFECTS 

Benign and malignant neoplasms were observed among dosed and control B6C3F1 mice (NCI 1978); 

however, in previous studies, each type has been observed as spontaneous lesions (NCI 1978). The 

incidence of hepatocellular adenomas (2/8, 11/49, and 19/50 in the 0, 5.4, and 10.7 mg/kg/day groups, 

respectively) in male mice provide equivocal evidence of an association between these lesions and 

guthion exposure. There were no statistically significant associations between tumor incidence and 

guthion exposure in female mice (NCI 1978). 

Under the conditions of the bioassay, NCI (1978) concluded that the incidences of neoplasms of the 

pancreatic islets and of the follicular cells of the thyroid in male rats provide suggestive, but insufficient, 

evidence of the carcinogenic potential of guthion in male rats. NCI (1978) concluded that guthion was 

not carcinogenic in male or female B6C3F1 mice or female Osborne-Mendel rats. The EPA Integrated 

Risk Information System of EPA (IRIS 2008) does not include an assessment for guthion. The 

International Agency for Research on Cancer (IARC) has not classified guthion as to its carcinogenicity 

(IARC 2006). 

3.2.3 Dermal Exposure 

The highest NOAEL values and all LOAEL values from each reliable study for appropriate end points in 

each species and duration category are recorded in Table 3-3. 

3.2.3.1 Death 

No information was located regarding mortality in humans following dermal exposure to guthion. 

Available acute dermal toxicity studies in animals indicate a wide range of LD50 values. For instance, 

Pasquet et al. (1976) calculated a dermal LD50 of 90 mg/kg for female rats administered receiving a single 

application of guthion. Gaines (1960) reported the same acute dermal LD50 value of 220 mg/kg for both 

male and female Sherman rats. In contrast, EPA (1978a) reported acute dermal LD50 values of 455 and 

222 mg/kg for male and female Sprague-Dawley rats, respectively. The highest reported acute dermal 

LD50 was 6,000 mg/kg reported by Skinner and Kilgore (1982) after a single dose of guthion was applied 

to the hind feet of male Swiss Webster mice. 
18 mg/kg

mg/kg

26

mg/kgmg/kg

14

mg/kg

15 mg/kg47

%volume

46

%volume

Table 3-3 Levels of Significant Exposure to Guthion - Dermal 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Death 

(SpragueDawley) Rat Once 

System NOAEL Less Serious 

LOAEL 

455 M 

mg/kg 

Serious 

(14 day LD50) 

Reference Chemical Form 

EPA 1978a 

222 F 

mg/kg 

(14 day LD50) 

(Sherman) Rat Once 

220 M 

mg/kg 

(14 day LD50) Gaines 1960 

220 F 

mg/kg 

(14 day LD50) 

(CD) Rat Once 

90 F 

mg/kg 

(10 day LD50) Pasquet et al. 1976 

(SwissWebster) Mouse Once 

6000 M 

mg/kg 

(24 hour LD50) Skinner and Kilgore 198

Immuno/ Lymphoret 

Human Once 

1 

%volume 

Lisi et al. 1987 

Human Once 

1 F 

%volume 

(allergic reaction to guthion in 1/64 fruit harvest workers) 

Sartorelli et al. 1999 
49

mg/kg

48

mg/kg/day 

33

mg/kg

16 mg/kg

Table 3-3 Levels of Significant Exposure to Guthion - Dermal (continued) 

Exposure/ LOAEL 

Duration/ 

Species Frequency Reference 

(Strain) (Route) System NOAEL Less Serious Serious Chemical Form 

Neurological 

Human Once 

0.0007 

mg/kg 

Franklin et al. 1981 

Human 1 x/d 

0.46 M 

mg/kg/day 

Schneider et al. 1994 

(SpragueDawley) Rat Once 

222 F 

mg/kg 

(signs of cholinergic poisoning: salivation, lacrimation, exophthalmus, defecation, urination, muscle fasciculations) 

EPA 1978a 

(SwissWebster) Mouse Once 

600 M 

mg/kg 

(24 hour ED50 for erythrocyte ChE activity) 

Skinner and Kilgore 198

ChE = cholinesterase; d = day(s); ED50 = median effective dose, 50% effect in population; F = Female; Immuno/Lymphoret = immunological/lymphoreticular; LD50 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; x = time(s) 
GUTHION 61 

3. HEALTH EFFECTS 

3.2.3.2 Systemic Effects 

No information was located regarding systemic effects in humans following dermal exposure to guthion. 

No information was located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, 

hepatic, endocrine, dermal, ocular, or metabolic effects in animals following dermal exposure to guthion. 

Hematological Effects. A 10% reduction in erythrocyte count was observed in male New Zealand 

white rabbits administered 20 mg guthion/kg/day, 5 days/week for 21 days; this effect was not seen at a 

dose level of 2 mg/kg/day in males or at doses up to and including 20 mg/kg/day in similarly-treated 

females (EPA 1999b). 

Renal Effects. Treatment-related increases in kidney weight and incidence of inflammatory renal 

changes were observed in male New Zealand white rabbits administered 20 mg guthion/kg/day, 

5 days/week for 21 days; these effects were not seen at a dose level of 2 mg/kg/day in males or at doses 

up to and including 20 mg/kg/day in similarly-treated females (EPA 1999b). 

Body Weight Effects. A 40–70% reduction in body weight gain was observed in female rabbits 

administered 20 mg guthion/kg/day, 5 days/week for 3 weeks; this effect was not seen at a dose level of 

2 mg/kg/day in females or at doses up to and including 20 mg/kg/day in similarly-treated males (EPA 

1999b). 

3.2.3.3 Immunological and Lymphoreticular Effects 

Patch tests were performed on 64 female workers (aged 17–59 years; mean, age 35 years) involved for an 

average of 11 years in the harvesting of cherries, peaches, olives, and grapes in Italy (Sartorelli et al. 

1999). Only one subject, who was without symptoms, showed a positive allergic reaction to guthion. In 

another study of 180 agricultural workers, 43 former agricultural workers, and 429 patients admitted to 

the clinic for nonallergic skin disorders, none of the subjects showed allergic or irritant reactions to 1% 

guthion patches applied to the upper back (Lisi et al. 1987). 

3.2.3.4 Neurological Effects 

Blood AChE activity was determined in approximately 34 peach harvest workers in California in 

1991 (Schneider et al. 1994). Workers were classified as “harvesters” (approximately 10) or “sorters” 

(approximately 24). Harvesters (all were male) entered orchards to pick fruit 51 days after treatment with 
GUTHION 62 

3. HEALTH EFFECTS 

guthion (50% active ingredient at 1.5 pounds active ingredient per 100 gallons of water per acre) and 

worked for 10 of the next 17 days, while sorters (males and females) went through fruit bins removing 

culls or fruit that was too green. The latter group was considered to have minimal exposure to foliar 

residues and served as a control group. There were no differences among harvesters or sorters in their 

whole blood AChE before workers entered the orchards; however, 14 and 23 days after entering the field, 

significant differences in AChE levels among these two groups were evident. The largest reduction in 

AChE observed in harvesters 14 days after entering the orchard was of approximately 16%. Similar 

reductions were reported 23 days after exposure, but conflicting data were offered by two separate 

laboratories. During the study period, there were no statistically significant (p>0.05) reductions in AChE 

in sorters, whereas two of four measurements showed significant (p<0.05) reductions in AChE in 

harvesters. No symptoms of organophosphorus insecticide poisoning were reported by any of the 

workers. 

A study was conducted with 17 orchardists who applied a single treatment of guthion in a wettable 

powder formulation (50% a.i.) in the South Okanagan Valley, British Columbia (Franklin et al. 1981). 

The amounts of guthion applied in this study ranged from approximately 1 to 5 kg. Respirators were 

worn by applicators. Based on analysis of guthion residues on patches, dermal exposure was estimated to 

range from 9 to 43 μg guthion/kg applied. A mean dermal exposure dose of 0.7 μg/kg was estimated 

based on anatomical regional deposition of guthion on the bodies of subjects, surface area estimates of 

these anatomical regions, and a reference body weight of 70 kg. Postexposure erythrocyte AChE activity 

appeared to be reduced 15% in the exposed workers; however, these alterations did not exceed the 

variation observed in the group of unexposed individuals (n=10) in the control group (Franklin et al. 

1981). 

A study was conducted of 21 male agricultural workers (ages 21–63; mean age 35.5 years) exposed to 

foliage-borne residues of guthion during peach-thinning operations in California (Kraus et al. 1977). 

Workers entered the peach orchards 14 days after they had been treated with a 50% wettable powder of 

guthion (50% a.i.) at a rate of 2 pounds a.i. per 100 gallons of water per acre. Mean whole blood ChE 

activity levels during the 5-day exposure period ranged from 90.1 to 95.6% of mean baseline (3-day 

preexposure) levels (Kraus et al. 1977). Erythrocyte AChE activity was not measured. Although 

postexposure examinations indicated a reduction in upper body reflex activity, it seems likely that the 

observation was due to fatigue from work-related exertion during thinning. There was no reduction in 

reflexes in the lower extremities (Kraus et al. 1977). 
GUTHION 63 

3. HEALTH EFFECTS 

Reductions in erythrocyte AChE activity were observed in a group of 20 agricultural workers (ages 18– 

58; median age 28.5 years) who entered California peach orchards 30 days after they had been treated 

with guthion (1.5 pounds a.i. per acre) (McCurdy et al. 1994). Three days after entering the treated fields, 

erythrocyte AChE activity was 7% lower than baseline levels in the same workers. After 44 days of 

fieldwork, erythrocyte AChE activity had decreased 19% from baseline levels (McCurdy et al. 1994). No 

clinical signs were reported by the authors. 

EPA (1978a) reported signs of cholinergic poisoning, such as salivation, lacrimation, exophthalmus, 

defecation, urination, and muscle fasciculations in male and female Sprague-Dawley rats administered 

lethal doses of guthion dermally. Although the precise doses at which these effects were observed were 

not provided, it was reported that the 14-day dermal LD50 values in male and female rats were 455 mg/kg 

(95% confidence interval [CI]: 301–687) and 222 mg/kg (95% CI 181–271), respectively. Skinner and 

Kilgore (1982) estimated that a single, dermal exposure to 600 mg/kg would elicit a 50% reduction in 

erythrocyte AChE activity in male Swiss-Webster mice. 

A 24–38% reduction in erythrocyte AChE activity was observed in male and female rabbits administered 

20 mg/kg/day dermally 5 days/week for 3 weeks; this effect was seen as early as day 10 following the 

initiation of treatment (EPA 1999b). 

Male rats were treated dermally with A 16–17% reduction in erythrocyte AChE activity (relative to 

control animals) was observed within 10–24 hours in male rats administered dermal applications of a 35% 

wettable powder formulation of guthion at a guthion equivalent dose of 5.6 mg/kg for up to 1 week (EPA 

1999b). There was no effect on erythrocyte AChE activity in rats of a 0.56 mg/kg group and no effect on 

plasma ChE activity at either dose level. 

3.2.3.5 Reproductive Effects 

No information was located regarding reproductive effects in humans or animals following dermal 

exposure to guthion. 

3.2.3.6 Developmental Effects 

García et al. (1998) studied the incidence of congenital malformations (nervous system defects, 

cardiovascular defects, oral clefts, epispadia or hypospadia, and musculoskeletal defects) in children born 

of fathers with occupational exposures to pesticides. Exposure was assessed via questionnaire. The odds 
GUTHION 64 

3. HEALTH EFFECTS 

ratio for the occurrence of birth defects in fathers (6 cases and 8 referent cases) exposed to guthion was 

0.71 (0.23–2.25), indicating that there was no evident association between the occurrence of birth defects 

and paternal exposure to guthion. 

3.2.3.7 Cancer 

No information was located regarding cancer in human or animals following dermal exposure to guthion. 

3.3 GENOTOXICITY 

In vivo evaluations of genotoxicity in humans were not located. The results of all available in vivo animal 

studies and in vitro tests are presented in Tables 3-4 and 3-5, respectively. Negative results were reported 

in a study of recessive lethality in Drosophila and two studies of micronuclei formation and dominant 

lethality in mice (Waters et al. 1982). The available in vitro genotoxicity data suggest that guthion is not 

genotoxic to prokaryotic organisms (Carere et al. 1978; Hrelia et al. 1990; Waters et al. 1982; Zeiger et al. 

1987). Six available in vitro studies with eukarytotic organisms (fungi and mammalian cells) showed 

positive results for genotoxic effects (Alam and Kasatiya 1976; Alam et al. 1974; Bianchi-Santamaria et 

al. 1997; Waters et al. 1982); results of five other in vitro assays were negative (Chen et al. 1982a, 1982b; 

Waters et al. 1982). 

3.4 TOXICOKINETICS 

3.4.1 Absorption 

No information was located regarding possible age-related differences in absorption of guthion following 

inhalation, oral, or dermal exposure. 

3.4.1.1 Inhalation Exposure 

Absorption of guthion via the inhalation pathway can be inferred from a study demonstrating reductions 

in erythrocyte AChE activity in rats exposed to guthion aerosols at 4.72 mg/m3

 for 2 weeks (Kimmerle 

1976). Absorption via the inhalation pathway appears to be rapid. Whole blood ChE activity was 

reduced by an average of 41% in male Sprague-Dawley rats following a 1-hour exposure to 39 mg/m3 

(EPA 1978a). 
GUTHION 65 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Guthion In Vivo 

Species (test system) End point Results Reference 

Drosophila melanogaster Recessive lethality – Waters et al. 1982 

Mammalian cells 

Mouse Micronuclei formation – Waters et al. 1982 

Mouse Dominant lethal – Waters et al. 1982 

– = negative result 
GUTHION 66 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of Guthion In Vitro 

Species (test system) End point Results Reference 

Prokaryotic organisms 

Salmonella typhimurium (TA1535, 

TA1536, TA1537, TA1538) 

S. typhimurium ((TA98, TA100, 

TA1535, TA1537, TA1538) 

S. typhimurium 

S. typhimurium (TA98, TA100, 

TA1535, TA1537) 

 Streptomyces coelicolor

 Escherichia coli 

Eukaryotic organisms

 Fungi 

 Saccharomyces cerevisiae 

 S. cerevisiae 

 S. cerevisiae 

 Mammalian cells 

Human cell lines WI–38 and 

HEp-2 

 Human lymphocytes 

Chinese hamster ovary cells 

(KI cell line) 

Chinese hamster ovary cells 

Reverse mutation – Carere et al. 1978 

Reverse mutation – Waters et al. 1982 

(with or without 

metabolic 

activation) 

Reverse mutation – Hrelia et al. 1990 

(with or without 

metabolic 

activation) 

Reverse mutation + Zeiger et al. 1987 

(weakly 

mutagenic in 

TA98; negative 

in others) 

Forward mutation – Carere et al. 1978 

Reverse mutation – Waters et al. 1982 

(with and without 

metabolic 

activation) 

Enhanced mitotic + Waters et al. 1982 

recombination (with and without 

metabolic 

activation) 

Gene conversion; – Waters et al. 1982 

crossing over (with and without 

metabolic 

activation) 

Enhanced mitotic + Hrelia et al. 1990 

crossing over (with metabolic 

activation) 

Chromosome breaks + Alam and Kasatiya 

1976 

Micronucleus + Bianchi-Santamaria et 

formation al. 1997 

Chromosome breaks + Alam et al. 1974 

Sister chromatid – Waters et al. 1982 

exchange (with and without 

metabolic 

activation) 
GUTHION 67 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of Guthion In Vitro 

Species (test system) End point Results Reference 

Chinese hamster ovary cells Sister chromatid – Chen et al. 1982a 

(V79 line) exchange (without 

metabolic 

activation) 

Chinese hamster ovary cells Sister chromatid – Chen et al. 1982b 

(V79 line) exchange (with metabolic 

activation) 

Mouse lymphoma cells Forward mutation + Waters et al. 1982 

(with and without 

metabolic 

activation) 

Human fetal lung fibroblasts Unscheduled DNA – Waters et al. 1982 

synthesis (with and without 

metabolic 

activation) 

– = negative result; + = positive result; DNA = deoxyribonucleic acid 
GUTHION 68 

3. HEALTH EFFECTS 

3.4.1.2 Oral Exposure 

No information was located regarding absorption of guthion in humans after oral exposure. Animal 

studies suggest that gastrointestinal absorption of guthion is rapid. Greater than 80% of the radioactivity 

from an 8 mg/kg oral dose of radiolabeled guthion was detected in the internal organs (other than 

gastrointestinal tract), urine, and exhaled air of rats at 6 hours posttreatment (Fakhr et al. 1996). 

3.4.1.3 Dermal Exposure 

Guthion is absorbed through the skin, as demonstrated by the urinary excretion of radiolabeled 

metabolites of guthion after the application of 4 μg guthion/cm2

 to forearms of six volunteers (Feldmann 

and Maibach 1974). Radiolabeled metabolites were detected in the urine as early as 4 hours 

postapplication; approximately 16% of the dose was excreted during 5 days postapplication. 

Dermal absorption of guthion has also been demonstrated in animals, as evidenced by excretion of 

guthion urinary metabolites following dermal exposure. Franklin et al. (1983) estimated 60% absorption 

of guthion from 24-hour dermal application (100–400 μg guthion) to the dorsal skin of male SpragueDawley rats, based on urinary recovery of dimethyl thiophosphate (DMTP); most of the urinary DMTP 

had been recovered by 24 hours postapplication. Nearly 5% of the radioactivity from a 35% wettable 

powder formulation of 14C-guthion, applied dermally to rats at a concentration resulting in an estimated 

dermal dose of 0.056 mg (a.i.)/kg, was recovered in the urine during 10 hours postdosing, indicating that 

the material was readily absorbed through the skin (Schroeder 1992). Based on measurements of total 

radioactivity recovered at 10 hours postdosing, it was estimated that >50% of the applied dose had been 

absorbed. 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

No human or animal data were located regarding distribution following inhalation exposure to guthion. 

No information was located regarding possible age-related differences in the distribution of absorbed 

guthion. 
GUTHION 69 

3. HEALTH EFFECTS 

3.4.2.2 Oral Exposure 

No data were located regarding distribution in humans following oral exposure to guthion. At 6 hours 

following single oral dosing of 14C-guthion (8 mg/kg) to rats, >50% of the radioactivity was detected in 

muscle tissue, approximately 2.4% in the liver, and 1% in the blood; other tissues and organs accounted 

for 0.1–0.8% of the radioactivity (Fakhr et al. 1996). By 48 hours postdosing, radioactivity was no longer 

detected in organs or tissues and approximately 71, 13, and 6 % of the administered radioactivity had 

been recovered in expired CO2, feces, and urine, respectively. 

3.4.2.3 Dermal Exposure 

Based on urinary excretion of radiolabeled metabolites of guthion following dermal application of 

guthion to volunteers (Feldmann and Maibach 1974), absorption, distribution, and metabolism of guthion 

is inferred. Similarly, distribution of guthion and its metabolites can be inferred based on recovery of 

radioactivity from urine and body tissues of laboratory animals following dermal application of 

14C-guthion (Franklin et al. 1983; Zendzian 2003). 

3.4.3 Metabolism 

A proposed metabolic scheme for guthion is presented in Figure 3-3. Although guthion (as parent 

compound) can function as an AChE inhibitor at relatively high concentrations (Buratti et al. 2003), its 

oxygenated metabolite (gutoxon) has long been considered to be the major source of AChE inhibition 

(Murphy and DuBois 1957). Results of in vitro studies using human liver microsomes indicate that the 

bioactivation of guthion to gutoxon (reaction 1 in Figure 3-3) is a two-phase process, characterized by 

separate low- and high-affinity constants, and catalyzed by cytochrome P450 isozymes CYP1A2, 

CYP3A4, and CYP 2B6 (Buratti et al. 2003). The CYP1A2 isozyme appears to be mainly involved in the 

high-affinity phase of desulfuration observed at relatively low guthion concentrations, whereas CYP3A4 

is closely related to the low-affinity phase and CYP2B6 is associated with both high- and low-affinity 

phases at a wide range of guthion concentrations. The efficient activation of guthion to gutoxon in whole 

liver homogenates of rat, mouse, or guinea pig requires NAD or NADP+G-6-P (Hitchcock and Murphy 

1971). The amounts of gutoxon equivalents formed in 15 minutes following the addition of guthion to 

whole liver homogenates (amended with NADP and G-6-P) of rats, mice, and guinea pigs were 0.69, 

0.59, and 0.66 nmol/10 mg liver tissue, respectively, indicating that these three species are similar in 

guthion activation efficiency. 
GUTHION 70 

3. HEALTH EFFECTS 

Figure 3-3. Proposed Metabolism of Guthion 

O S

OH

N S 

P (4) Di-demethylated guthion + GS CH3 + GS CH3 

N 

O CH3 dealkylation

N (GSH)

Mono-demethylated guthion 

CH3 CH3 O O 

O O

S P OH + HS C N S P SH + GS C N

H2 dealkylation H2 O N (3) O N (GSH) H N N 3C H3C 

MMBA 

N 

N 

N 

O 

S 

P 

S 

O 

O 

CH3 

CH3 

dearylation 

(GSH) 

CYP450 

(NADPH, O2) 

oxidative cleavage 

DMPDT 

(2) (5) 

DMTP 

Guthion

CYP450

(1) (NADPH, O2) 

oxidative desulfuration 

O O 

O CH3

P 

N S 

CYP450 O CH3

(NADPH, O2) N 

N

oxidative cleavage dearylation

Gutoxon (GSH)

(6) (8) CH3 O 

O 

CH3 O (GSH) O P SH + GS C N 

O (7) dea H2 lkylation O N 

O P OH + HS C N N 

H2 H3C

O N DMTP 

N

H3C 

DMP MMBA 

N 

N 

N 

O 

S 

P 

O 

O 

OH 

+ GS CH3 

CH3 

DMP = dimethyl phosphate; DMPDT = dimethyl phosphorodithioate; DMTP = dimethyl thiophosphate; 

MMBA = mercaptomethyl benzazimide 

Sources: adapted from Fakhr et al. 1996; Motoyama and Dauterman 1972 
GUTHION 71 

3. HEALTH EFFECTS 

Major metabolites of guthion in the 48-hour urine of rats orally administered parent compound include 

mercaptomethyl benzazimide (MMBA), mono- and di-demethylated guthion, benzazimide, dimethyl 

phosphorodithioate (DMPDT), DMTP, and two unknown metabolites (Fakhr et al. 1996). Neither 

guthion (as parent compound) nor gutoxon were detected in the urine of these rats. Analysis of the 

urinary metabolites indicates that guthion is detoxified via two major pathways. One pathway involves 

CYP450-mediated cleavage of the P-S-C bond to yield DMTP and MMBA (reaction 2 in Figure 3-3). 

The other pathway involves glutathione-mediated dealkylation via cleavage of the P-O-CH3 bond to yield 

mono-demethylated guthion and GS-CH3 (S-methyl glutathione) (reaction 3 in Figure 3-3), which may be 

further demethylated to di-demethylated guthion and S-methyl glutathione (reaction 4 in Figure 3-3). 

S-methyl glutathione may be further degraded to CO2, which may explain the relatively large amounts of 

14CO2 in expired air following oral administration of radiolabeled guthion to laboratory animals (see 

Section 3.4.4.2). The presence of DMPDT in the rat urine indicates that guthion may undergo 

glutathione-catalyzed dearylation to form DMPDT and glutathione-conjugated mercaptomethyl 

benzazimide (reaction 5 in Figure 3-3). Likely metabolic steps involved in the detoxification of gutoxon 

include CYP450-mediated cleavage of the P-S-C bond to yield dimethyl phosphate (DMP) and MMBA 

(reaction 6 in Figure 3-3), glutathione-mediated dealkylation via cleavage of the P-O-CH3 bond to yield 

demethylated guthion and S-methyl glutathione (reaction 7 in Figure 3-3), and glutathione-catalyzed 

dearylation to form DMTP and glutathione-conjugated mercaptomethyl benzazimide (reaction 8 in 

Figure 3-3). 

Glutathione has been implicated in the detoxification of guthion in mammals (Levine and Murphy 1977; 

Motoyama and Dauterman 1972; Sultatos and Woods 1988); however, some studies contradict this role 

(Sultatos and Woods 1988). Support for the role of glutathione in detoxification comes from the 

observations that, in mice and rats, the depletion of glutathione, such as by pretreatment with methyl 

iodide or diethyl maleate, potentiates the toxicity of many dimethyl-substituted organothiophosphate 

insecticides and that the administration of large doses of certain dimethyl-substituted 

organothiophosphates elicits decreases in hepatic glutathione content (Sultatos and Woods 1988). 

Incubation of guthion in mouse liver homogenates reduced glutathione levels by 25% (Levine and 

Murphy 1977), but when the oxidative cofactors NADP and G-6-P were added to the medium, 

glutathione levels remained at control levels during 90 minutes of incubation. However, when guthion 

and the oxidative cofactors were added to liver homogenates from mice that were treated with piperonyl 

butoxide (an inhibitor of microsomal mixed function oxidases), levels of glutathione were reduced to 

approximately 80% of control values. These data suggest that glutathione is significantly involved in the 

detoxification of guthion when oxidative metabolism is inhibited (Levine and Murphy 1977). Other 
GUTHION 72 

3. HEALTH EFFECTS 

results indicate that glutathione may not be required for detoxication of guthion. Sultatos and Woods 

(1988) demonstrated that, although depletion of hepatic glutathione in the mouse by pretreatment with 

diethyl maleate potentiated the acute toxicity of guthion, depletion of hepatic glutathione by pretreatment 

with buthionine sulfoximine did not (Sultatos and Woods 1988). 

Paraoxonase (PON1; serum A-esterase), an enzyme found in humans and other mammals, can hydrolyze 

the oxygen analogues of organophosphate insecticides such as parathion, chlorpyrifos, and diazinon, 

thereby reducing their toxicity (Costa et al. 1999). In humans, serum PON1 is a polymorphic enzyme that 

shows low, intermediate, or high activity based on the hydrolysis of paraoxon (Akgür et al. 1999). 

However, PON1 does not appear to be involved in the hydrolysis of gutoxon because there was no 

difference in the inhibition of brain cholinesterase among homozygous wild (PON1 +/+) or knockout 

(PON1 -/-) mice treated with guthion (Costa et al. 1999). 

No information was located regarding possible age-related differences in guthion metabolism. 

3.4.4 Elimination and Excretion 

The urinary metabolites, DMPDT, DMTP, and DMP, were detected in the urine of individuals (88 men, 

11 women; ages 16–59 years) who resided near an area where guthion was used but who were not known 

to be occupationally exposed to guthion (Aprea et al. 1994). The total excretion of these urinary 

metabolites (DMPDT + DMTP + DMP) had a geometric mean and standard deviation of 145 and 

2.3 nmol/g creatinine, respectively, with a range of values of 5.5–884.5 nmol/g creatinine (Aprea et al. 

1994). However, these metabolites are not specific to guthion exposure. 

No information was located regarding possible age-related differences in elimination and excretion of 

guthion and its metabolites. 

3.4.4.1 Inhalation Exposure 

No information was located on the elimination and excretion of guthion in human or animals following 

inhalation exposure. 
GUTHION 73 

3. HEALTH EFFECTS 

3.4.4.2 Oral Exposure 

Guthion is rapidly metabolized and eliminated, as evidenced by the appearance of 22, 7.5, and 2.3% of 

the radioactivity from a single oral dose of 8 mg/kg of 14C-guthion (labeled at the two methyl groups) in 

expired air (as 14CO2), feces, and urine of rats by 6 hours postdosing (Fakhr et al. 1996). Approximately 

63, 11, and 6%, respectively, had been excreted by 24 hours postdosing; by 48 hours postdosing, total 

excretion of radioactivity by these routes had accounted for 90% of the administered dose. Major 

metabolites of guthion in the 48-hour urine included MMBA, mono- and di-demethylated guthion, 

benzazimide, DMPDT, DMTP, and two unknown metabolites. A total of seven urinary metabolites 

contained radioactivity from labeled methyl groups. Several urinary metabolites were not radiolabeled; 

these included MMBA, di-demethylated guthion, benzazimide, and other compounds. Neither guthion 

(as parent compound) nor gutoxon were detected in the urine. 

3.4.4.3 Dermal Exposure 

Urinary excretion of radiolabeled metabolites of guthion was detected after application of 4 μg 

guthion/cm2

 to the ventral forearm of six volunteers (Feldmann and Maibach 1974). The treated areas of 

the forearms were not protected and the subjects were asked not to wash the area for 24 hours. 

Radiolabeled metabolites could be detected in the urine ≤4 hours after application of the insecticide. The 

urinary excretion rate of guthion metabolites increased from 0.04% dose/hour in the first 4 hours after 

dosing to a maximum of 0.29% dose/hour at 8–12 hours after the dose had been applied (Feldmann and 

Maibach 1974). After that time, the excretion rate decreased until it reached 0.04% dose/hour 96– 

120 hours after the dose had been applied. Approximately 16% of the dose was excreted within the 

120-hour urinary sampling period (Feldmann and Maibach 1974). The urinary excretion values were 

corrected for guthion absorption efficiency as determined in a preliminary study where the subjects were 

administered a single, intravenous dose of 1 μCi of radiolabeled guthion (Feldmann and Maibach 1974). 

The latter study showed that approximately 70% of the intravenous dose was excreted within 120 hours, 

with a half-life of 30 hours. Urinary excretion of the radiolabeled residues of intravenously-administered 

guthion was faster than observed with the dermally-applied insecticide, the former reaching 1.6% 

dose/hour 8–12 hours after administration (Feldmann and Maibach 1974). 

Approximately 60% of the guthion doses (100–400 μg/rat) applied to a shaved area (2.6 cm2

) of the 

dorsal skin of male Sprague-Dawley rats was recovered in urine as DMTP (Franklin et al. 1983). The 

authors speculated that the calculation of dermal absorption of guthion based on the detection of DMTP in 

urine may lead to underestimates of absorption because DMTP constitutes only about 30% of the total 
GUTHION 74 

3. HEALTH EFFECTS 

alkyl phosphates excreted in urine after exposure to guthion. A linear relationship (r=0.943) between 

guthion doses and total DMTP output suggests that the capacity of the metabolic pathways was not 

exceeded at the doses administered. Franklin et al. (1986) briefly presented the results of a study with 

human subjects (two subjects per dose) who were administered guthion on the forehead at 500– 

6,000 μg/person (approximately 7–86 μg/kg). By 72 hours postdosing, the urinary excretion of DMTP 

had accounted for 5–17% of the administered dose. In general, increasing cumulative excretion was 

observed with increasing doses. Approximately 26 and 10% of the radioactivity from a 35% wettable 

powder formulation of 14C-guthion, applied dermally to rats at a concentration resulting in an estimated 

dermal dose of 0.056 mg (a.i.)/kg and rinsed 10 hours later, was recovered in the 7-day urine and feces, 

respectively (Schroeder 1992). 

3.4.4.4 Other Routes of Exposure 

The urinary recovery of metabolites observed in a study with human subjects administered a single 

intravenous dose of radiolabeled guthion (1 μCi) showed an initial peak (1.5% dose/hour) during 4 hours 

postdosing, which was followed by a drop in excretion and a second peak (1.6% dose/hour) 812 hours 

postdosing (Feldmann and Maibach 1974). The urinary output of radiolabeled guthion metabolites after a 

1 μCi intramuscular dose in rats showed two peaks in urinary excretion of the administered dose, one 

4 hours postdosing (approximately 13% of the dose) and a higher peak (approximately 20% of the dose) 

at 24 hours postdosing, followed by a rapid decrease in output to very low levels after 120 hours (Franklin 

et al. 1983). 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 
GUTHION 75 

3. HEALTH EFFECTS 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-4 shows a conceptualized representation of a PBPK model. 

If PBPK models for guthion exist, the overall results and individual models are discussed in this section 

in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations. 
GUTHION 76 

3. HEALTH EFFECTS 

Figure 3-4. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax Km 

Ingestion 

Inhaled chemical Exhaled chemical 

GI 

Tract 

Feces 

Urine

 Chemicals in air 

contacting skin 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan et al. 1994 
GUTHION 77 

3. HEALTH EFFECTS 

A PBPK model for guthion was not located. Feldmann and Maibach (1974) conducted a study of the 

urinary excretion of radiolabeled metabolites of guthion after application of 4 μg guthion/cm2

 to the 

ventral forearm of six volunteers. These data were used to develop a toxicokinetic model of the 

elimination of guthion based on the urinary elimination of alkylphosphate metabolites (Carrier and Brunet 

1999). The model, which does not include physiological details, predicted that the maximum body 

burdens of guthion after a single, 5-hour exposure or after repeated daily exposures for nine consecutive 

days were 73 and 208%, respectively, of the absorbed daily dose. The maximum body burden after a 

single exposure was predicted to occur 17 hours after the dose was administered. In the case of repeated 

doses, the body burden increased at an initially rapid rate and continued to increase until it reached 

steady-state after approximately nine daily doses; the rate of urinary excretion of guthion metabolites was 

predicted to reach steady state by day 9 as well. The rate of urinary excretion of metabolites after 

repeated doses was 3 times higher than after a single dose. The model was also used to estimate that 76% 

of the administered dose of guthion is excreted in the urine within 20 days after a single, 5-hour exposure. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

As discussed in detail in Section 3.4 (Toxicokinetics), guthion is readily absorbed and rapidly 

metabolized and eliminated following inhalation, oral, or dermal exposure. No studies were located in 

which mechanisms of absorption were assessed for guthion. It is expected that absorption is 

accomplished via passive diffusion. No information was located regarding mechanisms of distribution of 

absorbed guthion. However, other organophosphorus pesticides, such as diazinon, parathion, and methyl 

parathion, are known to bind reversibly to plasma proteins. It is generally understood that guthion does 

not appreciably accumulate in any specific body tissues and that absorbed guthion is rapidly metabolized 

and eliminated. No information was located regarding mechanisms of elimination and excretion of parent 

compound or metabolites of guthion. 

3.5.2 Mechanisms of Toxicity 

The most salient systemic effects of exposure to guthion are related to its direct effect on the nervous 

system and the secondary effects that result from it. The direct manner in which guthion exerts its 

systemic effects is through inhibition of ChE, specifically AChE in the central and peripheral nervous 

system. AChE is also present in erythrocytes. Thus, inhibition of erythrocyte AChE is commonly used 

as a surrogate indicator of the extent of inhibition of neural AChE. In addition, cholinesterases can be 
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found in plasma. In humans, plasma ChE is almost exclusively composed of butyrylcholinesterase. 

Although butyrylcholinesterase is capable of hydrolyzing acetylcholine and butyrylcholine in vitro, the 

in vivo substrate of plasma ChE is unknown. Guthion is bioactivated in vivo and in vitro to its oxygen 

analog form, variably referred to as gutoxon or azinphos-methyl oxon (Buratti et al. 2003; Hitchcock and 

Murphy 1971; Sultatos and Woods 1988). Gutoxon reacts with a serine hydroxyl group at the active site 

of AChE, rendering it largely inhibited and unreactive. Under normal circumstances, AChE rapidly and 

efficiently degrades the neurotransmitter acetylcholine following its release at the nerve synapse or at a 

neuromuscular junction; however, the inhibited AChE enzyme cannot degrade acetylcholine and the 

neurotransmitter accumulates at the ending of cholinergic nerves with the ensuing continual stimulation 

of electrical activity (Carrier and Brunet 1999). Cholinergic nerves play an important role in the normal 

function of the neuromuscular, central nervous, endocrine, immunological, and respiratory systems 

(Carrier and Brunet 1999). Thus, the inhibition of the enzyme AChE by gutoxon may have profound and 

wide-ranging systemic effects. Acetylcholine can be found in the autonomic nervous system, the somatic 

motor nervous system, and in the central nervous system. In the autonomic nervous system, 

accumulation of acetylcholine leads to the overstimulation of the muscarinic receptors of the 

parasympathetic nervous system, which can lead to effects on the exocrine glands (increased salivation, 

perspiration, lacrimation), eyes (miosis, blurred vision), gastrointestinal tract (nausea, vomiting, diarrhea), 

respiratory system (excessive bronchial secretions, wheezing, and tightness of chest), and cardiovascular 

system (bradychardia, decrease in blood pressure) (Ecobichon 1995). Stimulation of the nicotinic 

receptors in the parasympathetic or sympathetic nervous system may also cause adverse effects on the 

cardiovascular system such as tachycardia, pallor, and increased blood pressure. In the somatic nervous 

system, nerve fibers innervate the skeletal muscles motor end-plates. Accumulation of acetylcholine in 

the somatic nervous system may be manifested as muscle fasciculations, cramps, paralysis, and flaccid or 

rigid tone, among other signs and symptoms. Overstimulation of the nerves in the central nervous 

system, specifically the acetylcholine receptors of the brain, by the accumulation of acetylcholine may 

result in lethargy, drowsiness, and mental confusion among other effects. More severe effects on the 

central nervous system include a state of coma without reflexes, depression of the respiratory centers, and 

cyanosis (Ecobichon 1995). It has been recognized that, after repeated exposures to organophosphate 

insecticides, humans and other animal species may develop tolerance to the appearance of cholinergic 

signs (Costa et al. 1982). It has been proposed that this tolerance to the effect of excess acetylcholine 

develops by the down-regulation of postsynaptic cholinergic receptors. This reduces the apparent 

cholinergic symptoms even in the presence of marked reductions in erythrocyte AChE activity (Sultatos 

1994). 
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Other esterases, such as carboxylesterase, may be involved in the toxicity of organophosphate 

insecticides. For instance, malaoxon, the oxon form of malathion, is hydrolyzed by a carboxylesterase. 

When the carboxylesterase is inhibited, the acute toxicity of malaoxon increases (Agency for Toxic 

Substances and Disease Registry 2003); however, no data were located to suggest a similar role for 

carboxylesterases in guthion toxicity. 

3.5.3 Animal-to-Human Extrapolations 

No studies were located that directly studied the comparative toxicokinetics of guthion in animals and 

humans. Nevertheless, available information suggests that the toxicokinetics of guthion in animals and 

humans are generally similar. Recent work suggests that the desulfuration of guthion to gutoxon in 

human liver microsomes is largely effected by at least three cytochromes (CYP1A2, CYP3A4, and 

CYP2B6), which show different affinities for the substrate (Buratti et al. 2003). Significant variations in 

the activities of these cytochromes among humans and laboratory animal species would be expected to 

result in notable differences in guthion metabolism. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 
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similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

Although no studies were located regarding endocrine disruption in humans or animals after exposure to 

guthion, the studies discussed in this toxicological profile (Holzum 1990; Kavlock et al. 1985; NCI 1978; 

Short et al. 1980; Vos et al. 1983) do not suggest that guthion exerts consistent, clinically-evident effects 

on the neuroendocrine axis. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 
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and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

No human data are available regarding possible age-related differences in susceptibility to guthion 

toxicity. Developmental toxicity studies in rats and rabbits have shown no evidence of increased 

sensitivity of fetuses as compared to maternal animals following in utero exposure. Furthermore, singleand two-generation reproductive toxicity studies in rats showed no increased susceptibility of pups versus 

adults (EPA 1999b). Additional relevant information from other organophosphorus pesticides is 

presented below in order to draw inferences as the data allow. Acute dermal, inhalation, and oral 

exposures to the organophosphorus pesticide methyl parathion has resulted in typical signs of 

organophosphate poisoning including reductions in plasma and erythrocyte AChE activity, alterations in 
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the function of nervous, cardiac, pulmonary, and gastrointestinal systems, and deaths in adults (Fazekas 

1971; Fazekas and Rengei 1964) as well as in children (Dean et al. 1984). These findings suggest that 

adults and children share similar targets of toxicity from exposure to methyl parathion. These findings 

might apply to guthion given the similarities in the mode of action between the two pesticides; however, 

it should be noted that there are no reported poisonings of children exposed to guthion. The neurotoxicity 

of guthion is dependent on its bioactivation via a cytochrome P450 mediated desulfuration to the oxon 

form (Buratti et al. 2003). Recent work suggests that the desulfuration of guthion to the oxon form by 

cytochromes in human liver microsomes proceeds via two steps, each characterized by high and low 

affinities; that more than one cytochrome may be involved in the desulfuration process; and that the role 

of different cytochromes in desulfuration may be dependent on the guthion concentration (Buratti et al. 

2003). Some P450 isozymes are regulated differently during development than during adulthood (Leeder 

and Kearns 1997), but information specific to guthion is not available. Nevertheless, it is conceivable that 

developmental differences in the regulation of P450 isozymes could lead to differences in the 

susceptibility of children to guthion toxicity. It is known that acetylcholine, acetylcholinesterase, and 

butyrylcholinesterase are involved in the development of the nervous system (Brimijoin and 

Koenigsberger 1999; Layer 1990; Layer and Willbold 1994) and that some of this development is not 

completed until adulthood. Thus, it is plausible that by interfering with the normal ChE function, guthion 

might elicit adverse developmental effects. Garcia-Lopez and Monteoliva (1988) showed that erythrocyte 

AChE activity increases with increasing age, starting at birth and until >60 years of age. It is conceivable 

that these changes in AChE activity could elicit age-related differences in responses to guthion poisoning. 

Although some studies have reported reductions in pup weight and survival, brain weight, and ChE 

activity, and increased incidence of supernumerary ribs and malaligned sternebrae in offspring of 

pregnant mice or rats (Holzum 1990; Kavlock et al. 1985; Short et al. 1980), these effects are typically 

observed at maternally toxic doses. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 
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substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself, substance-specific metabolites in 

readily obtainable body fluid(s), or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous 

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to guthion are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by guthion are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Guthion 

The ideal biomarker for the quantification of exposure to guthion would be specific to the chemical of 

interest and would probably be the insecticide itself or a metabolite that could only be detected after 

exposure to guthion. It has been shown that DMPDT, DMTP, and DMP are metabolic products of the in 

vivo degradation of guthion (Carrier and Brunet 1999) and have been detected in urine of humans under 
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field and experimental conditions after dermal or otherwise unspecified exposure. For instance, Franklin 

et al. (1986) detected DMTP in the urine of volunteers 72 hours after they were administered guthion at 

500–6,000 μg/person (approximately 7–86 μg/kg) on the forehead. Urinary excretion of the metabolites 

DMPDT, DMTP, and DMP was detected in a group (n=99) of individuals not known to be occupationally 

exposed to guthion (Aprea et al. 1994). These individuals may have been exposed to guthion from the 

diet, but exposure estimates were not provided. The total excretion of DMPDT + DMTP + DMP 

exhibited a range of 5.5–884.5 nmol/g creatinine, a geometric mean of 145 nmol/g creatinine, and a 

standard deviation of 2.3 (Aprea et al. 1994). Unfortunately, these metabolites are of limited use as 

biomarkers of exposure because they can be detected after exposure to other organophosphate insecticides 

as well. Neither guthion nor gutoxon were detected in urine collected during 48 hours from rats 

administered a single oral dose of guthion at 8 mg/kg (Fakhr et al. 1996). No studies were located 

regarding the usefulness of guthion or gutoxon in blood of exposed animals or humans as biomarkers of 

exposure. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Guthion 

Guthion-induced changes in erythrocyte AChE and plasma ChE activity do not serve as biomarkers of 

effect that are specific to guthion poisoning because such changes are common to numerous 

organophosphorus and carbamate ester insecticides. In addition, the large degree of variability in ChE 

activity in human populations suggests that caution should be exercised when comparing ChE activities 

from exposed populations, such as agricultural workers, and reference populations. For example, activity 

levels at the upper limit of the normal range may be 200% higher than those at the lowest level (Maroni et 

al. 2000). Long-term sequential monitoring of ChE activity in populations of interest may allow a more 

accurate confirmation of enzyme inhibition (Coye et al. 1987). 

Organophosphate poisoning may be categorized as mild, moderate, or severe based on the clinical signs 

and symptoms of poisoning and the measured reductions in ChE activity. Mild cases of poisoning, in 

which the patient retains the ability to move, may occur when plasma ChE activity levels are 50–80% 

below normal; moderate cases of poisoning in which the patient has lost the ability to walk can be seen 

with activity levels 80–90% below normal; and severe poisoning with respiratory distress and 

unconsciousness may be seen at plasma ChE activity levels >90% below normal (Tafuri and Roberts 

1987). Methods for measuring erythrocyte and plasma cholinesterase are presented in Chapter 7. 
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3.9 INTERACTIONS WITH OTHER CHEMICALS 

Chemicals that alter the metabolism of guthion, particularly its activation to gutoxon and the degradation 

of guthion or gutoxon, can be expected to alter the toxicity of guthion. Piperonyl butoxide, an inhibitor of 

microsomal mixed function oxidases, inhibited the activation of guthion to gutoxon in vitro (Levine and 

Murphy 1977). Although the activation and detoxification of guthion in vivo interact in complex ways, it 

would be expected that inhibition of the activation of guthion to its oxygen analog would result in a 

reduction of the anticholinesterase toxicity of guthion. 

Given that guthion shares essential aspects of its mechanism of toxic action with many other 

organophosphate (and carbamate ester) insecticides, it is reasonable to expect that the toxicity of guthion 

and other organophosphate insecticides would show at least additive effects under concurrent exposure 

conditions. Dose additivity for anticholinesterase effect was observed in vitro when rat brain AChE was 

incubated with the guthion oxygen analog and chlorpyrifos-oxon simultaneously (Richardson et al. 2001). 

The anticholinesterase effect was nonlinear when the two chemicals were added to serum ChE. Greaterthan-additive effects were observed when the two bioactive chemicals were added sequentially at high 

concentrations to rat serum or brain incubation media. In 2002, the EPA completed a Revised OP 

Cumulative Risk Assessment (EPA 2002) to address cumulative risk from exposure to organophosphate 

insecticides in food, water, and domestic applications. The reader should refer to that document, 

available on-line, for an in-depth discussion of the issue of cumulative risk from exposure to 

organophosphate insecticides. 

Pyridostigmine is an anticholinesterase drug used in the treatment of symptoms of myasthenia gravis 

(Taylor 2001). Individuals who are undergoing medical treatment with pyridostigmine or other anti-ChE 

drugs on an ongoing basis and are concurrently exposed to guthion might experience an additional 

inhibition of AChE elicited by guthion; however, the extent of the additional reduction in AChE activity 

elicited by guthion and the clinical neurotoxic effects, if any, of this additional reduction in AChE activity 

are uncertain. Pyridostigmine was also used in 1990 during the Persian Gulf War to protect troops from 

poisoning with the nerve agent Soman (Taylor 2001). However, when administered prophylactically to 

U.S. troops, treatment with pyridostigmine would be discontinued upon exposure to Soman and the 

exposed personnel would be treated immediately with the antidotes atropine and pralidoxime. 

The antagonistic effect of some drugs on the anticholinesterase action of organophosphates has been 

applied to great advantage in the emergency treatment of acute organophosphate intoxications in humans. 
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Atropine, for instance, is a potent blocker of the activity of acetylcholine at muscarinic nerve receptors. 

Atropine reduces the clinical effects associated with the stimulation of the parasympathetic nervous 

system by excess acetylcholine. The antidote pralidoxime (2-PAM), can not only reverse the effect of 

cholinergic nicotinic overstimulation (such as skeletal muscle fasciculation, muscle weakness, and 

paralysis of respiratory muscles), but can also reactivate phosphorylated cholinesterase (Tafuri and 

Roberts 1987). 

In vitro studies showed that guthion activation proceeded more rapidly and gutoxon degradation was 

markedly reduced when fluoride (0.01 M) was added to rat liver microsomes amended with cofactors and 

either guthion or gutoxon (Dahm et al. 1962). It has been postulated that fluoride interferes with the 

activity of phosphatases (Murphy and Dubois 1957). These studies indicate that alterations in the balance 

between the activation of guthion and the degradation of guthion and gutoxon can be elicited in vitro. It 

may reasonably be expected that these alterations might also affect the anticholinesterase activity of 

gutoxon in vivo. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to guthion than will most persons 

exposed to the same level of guthion in the environment. Reasons may include genetic makeup, age, 

health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These 

parameters result in reduced detoxification or excretion of guthion or compromised function of organs 

affected by guthion. Populations who are at greater risk due to their unusually high exposure to guthion 

are discussed in Section 6.7, Populations with Potentially High Exposures. 

No information was located regarding variability in susceptibility among different populations exposed to 

guthion. However, individuals who respond to the anticholinesterase effects of organophosphates more 

rapidly and with greater reductions in ChE activity might be expected to be more susceptible to the 

neurotoxic effects of guthion. These responses may be genetic in origin or may be due to differences in 

development or life style factors, such as nutrition or behavior, or to preexisting disease states. 

Individuals with hereditary low plasma ChE levels (Kalow 1956; Lehmann and Ryan 1956) and those 

with unusually low levels of erythrocyte acetylcholinesterase, such as individuals with paroxysmal 

nocturnal hemoglobinuria (Auditore and Hartmann 1959), would have increased susceptibility to the 

effects of anticholinesterase agents such as guthion. During pregnancy, women have exhibited 

significantly decreased plasma ChE activity levels (De Peyster et al. 1993; Evans and Wroe 1980; Evans 
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et al. 1988; Howard et al. 1978; Sanz et al. 1991; Venkataraman et al. 1990) and significantly increased 

erythrocyte AChE levels (De Peyster et al. 1993; Sanz et al. 1991; Venkataraman et al. 1990), but it is not 

known whether these differences might make pregnant women more susceptible to guthion toxicity. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to guthion. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to guthion. When specific 

exposures have occurred, poison control centers and medical toxicologists should be consulted for 

medical advice. The following texts provide specific information about treatment following exposures to 

organophosphate pesticides: 

Carlton FB, Simpson WM, Haddad LM. 1998. The organophosphates and other insecticides. In: 

Haddad LM, Shannon MW, Winchester JF, eds. Clinical management of poisoning and drug overdose. 

3rd ed. Philadelphia, PA: W B Saunders Company, 836-845. 

Goldfrank LR, Flomenbaum NE, Lewin NA, et al., eds. 1998. Goldfrank's toxicologic emergencies. 6th 

ed. Stamford, CT: Appleton and Lange, 836-843. 

Osmundson M. 1998. Insecticides and pesticides. In: Viccellio P, ed. Emergency toxicology. 2nd ed. 

Philadelphia, PA: Lippincott-Raven Publishers, 401-413. 

3.11.1 Reducing Peak Absorption Following Exposure 

No information specific to guthion was located regarding methods for reducing guthion toxicity. The 

following information for reducing the toxicity of organophosphates in general is considered relevant to 

guthion and was obtained from the texts listed above. Respiratory distress is a common effect of 

poisoning after inhalation of organophosphates and its treatment is mostly supportive. Under some 

circumstances intubation may be necessary to facilitate control of secretions. Washing the skin with 

copious amounts of soap and water is recommended in cases of dermal contamination with 

organophosphates. This first wash may be followed by a second washing with ethyl alcohol. Exposure of 

the eyes should be immediately treated by copious irrigation of the eye with normal saline or lactated 

Ringer’s solution (Aaron and Howland 1998). Contaminated clothing including leather garments should 

be destroyed. Activated charcoal is recommended for many organophosphates after oral exposure; 

however, Carlton et al. (1998) pointed out that this treatment may lack efficiency with some 

organophosphates. Ipecac should not be used for organophosphate poisoning (Osmundson 1998). 
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Cathartics may be unnecessary as intestinal motility is greatly increased. Gastric lavage may be 

performed with care, as organic solvent vehicles may cause pneumonitis if inhaled during the procedure. 

3.11.2 Reducing Body Burden 

No information was located regarding the reduction of the body burden of guthion. However, it should be 

pointed out that the body burden of guthion is expected to be rapidly reduced upon cessation of exposure 

to the insecticide. There were no detectable guthion metabolites in muscle or internal organs in rats 

48 hours after being administered an 8 mg/kg dose of radiolabeled guthion by gavage (Fakhr et al. 1996). 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Information on the interference with the mechanism of action for toxic effects of guthion was not located. 

Thus, information pertinent to organophosphate pesticides in general was extracted from the texts listed 

above. Organophosphate poisoning is commonly treated by administration of atropine and pralidoxime 

(2-PAM). Atropine is a competitive antagonist at muscarinic receptor sites and is helpful in drying 

excessive secretions, especially from the tracheobronchial tree. Although atropine crosses the blood-brain 

barrier and thus also treats the central nervous system effects, it does not antagonize nicotinic effects. 

Initial doses of 1–2 mg for an adult and 0.05 mg/kg for children, preferably by the intravenous route, have 

been recommended. Treatment may be repeated every 15–30 minutes until signs of atropinization occur. 

Glycopyrrolate, a quaternary ammonium compound, has also been used instead of atropine (Bardin and 

Van Eeden 1990). Glycopyrrolate does not cross the blood-brain barrier and has fewer central nervous 

system effects than atropine. Nicotinic effects such as muscle weakness and respiratory depression from 

organophosphate poisoning are commonly treated by administration of 2-PAM. 2-PAM is a quaternary 

amine oxime that can restore enzymatic activity by reversing the phosphorylation of acetylcholinesterase. 

2-PAM and other oximes function by nucleophilic attack on the phosphorylated enzyme; the oximephosphonate is then split off, leaving the regenerated enzyme. Moreover, 2-PAM has an anticholinergic 

effect and may prevent continued toxicity by detoxifying the organophosphate molecule (Carlton et al. 

1998). 2-PAM should be administered as soon as a diagnosis of poisoning is made. The initial dose is 1– 

2 g for adults and 25–50 mg/kg for children, administered intravenously over 30–60 minutes. The dose 

can be repeated in 1 hour and then every 8–12 hours until clinical signs have diminished and the patient 

does not require atropine. Since enzyme regeneration depends on plasma levels of the organophosphate, 

some patients may require multiple doses. A 2-PAM serum level of 4 μg/L is suggested as the minimum 

therapeutic threshold. 2-PAM is considered a safe drug with few side effects; however, high doses of 

2-PAM can cause neuromuscular blockade and inhibition of AChE, although these effects are minimal at 
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the recommended antidotal doses (Taylor 2001). An intravenous administration rate of 2-PAM 

>500 mg/minute can result in mild weakness, blurred vision, diplopia, dizziness, headache, nausea, and 

tachycardia (Taylor 2001). 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of guthion is available. Where adequate information is not 

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of guthion. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of Guthion 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

guthion are summarized in Figure 3-5. The purpose of this figure is to illustrate the existing information 

concerning the health effects of guthion. Each dot in the figure indicates that one or more studies provide 

information associated with that particular effect. The dot does not necessarily imply anything about the 

quality of the study or studies, nor should missing information in this figure be interpreted as a “data 

need”. A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data 

Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is 

substance-specific information necessary to conduct comprehensive public health assessments. 

Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from 

the scientific literature. 

Human and animal studies suggest that inhibition of AChE activity is the most sensitive end point of 

guthion toxicity. Inhibition of AChE activity has been observed after inhalation, oral, and dermal 

exposures to guthion. The inhibition of AChE activity by guthion is dose-related, but is not strongly 
GUTHION 90 

3. HEALTH EFFECTS 

Figure 3-5. Existing Information on Health Effects of Guthion 

Death 

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 
GUTHION 91 

3. HEALTH EFFECTS 

influenced by duration of exposure. The inhibition of nervous system AChE leads to the accumulation of 

the neurotransmitter acetylcholine at the ending of cholinergic nerves with the ensuing continual 

stimulation of electrical activity (Carrier and Brunet 1999). Erythrocyte AChE is analogous to nervous 

system AChE and inhibition of the former is correlated with clinical toxicity in the nervous system 

(Carrier and Brunet 1999). In humans and animals, significant inhibition of erythrocyte AChE activity 

occurs at doses that are several times lower than doses eliciting clinical signs and symptoms. 

In humans, mild, moderate, and severe poisoning with organophosphate insecticides corresponds to ChE 

activity reductions to 20–50, 10–20, and <10% of normal levels, respectively (Aaron and Howland 1998). 

Despite these general guidelines, it should be kept in mind that a single ChE activity measurement cannot 

confirm or exclude exposure to organophosphate insecticides given the large variation in the normal 

levels of ChE activity in the general population. 

There is a paucity of controlled studies of humans exposed to guthion. The only controlled studies of 

humans exposed orally to guthion (Rider and Puletti 1969; Rider et al. 1970, 1971, 1972) remain 

unpublished, and limited information from them is available only in abstracts; however, a small number 

of dermal absorption and dermatologic studies in humans and studies of agricultural workers exposed to 

guthion during application are available. 

Neurological, systemic, reproductive, and developmental effects have been evaluated in dogs, rats, or 

mice after acute-, intermediate-, and chronic-duration exposures to guthion by inhalation, oral, and dermal 

routes. The potential carcinogenicity of guthion has also been evaluated. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. No controlled, acute toxicity studies in humans exposed to guthion 

orally or by inhalation were available. Studies of agricultural workers exposed to guthion were located 

(Franklin et al. 1981; Kraus et al. 1977; Schneider et al. 1994) as were studies of the dermal absorption of 

guthion in volunteers (Feldmann and Maibach 1974). Guthion is absorbed when applied dermally in 

humans as demonstrated by the urinary excretion of radiolabeled metabolites of guthion after a single 

application of guthion to the forearms of volunteers (Feldmann and Maibach 1974). Feldmann and 

Maibach (1974) examined the excretion of radiolabeled guthion metabolites, but the study was not 

designed to identify toxic end points. Acute-duration studies in rats and mice evaluated the neurotoxic, 

systemic, reproductive, and developmental effects of guthion following inhalation, oral, and dermal 
GUTHION 92 

3. HEALTH EFFECTS 

exposure (Astroff and Young 1998; EPA 1978a; Gaines 1960; Kavlock et al. 1985; Kimmerle 1976; 

Pasquet et al. 1976; Short et al. 1980; Skinner and Kilgore 1982; Su et al. 1971). ATSDR derived an 

acute-duration inhalation MRL based on the study by Kimmerle (1976), which is the only available acuteduration inhalation study with guthion in which activity levels of erythrocyte AChE were determined. 

Clinical signs at lethal doses were reported after a 1-hour exposure of rats to guthion, but erythrocyte 

AChE activity was not determined (EPA 1978a). An additional acute-duration inhalation study in mice or 

rats conducted at doses ranging from the low doses in Kimmerle (1976) to the higher doses used in EPA 

(1978a) would be useful to confirm the results of Kimmerle (1976) and to allow a better understanding of 

the dose-response curve for reductions in erythrocyte AChE activity and the onset of clinical signs of 

neurotoxicity. ATSDR derived an acute-duration oral MRL based on the study of Astroff and Young 

(1998). Additional acute-duration studies of the oral toxicity of guthion are not considered necessary at 

this time. The large variation in dermal LD50 values (EPA 1978a; Gaines 1960; Pasquet et al. 1976; 

Skinner and Kilgore 1982) could be due to differences in absorption related to experimental methods. An 

additional acute-duration dermal study in mice or rats would be useful to better understand the dose 

response curve for reductions in erythrocyte AChE activity and the onset of clinical signs of 

neurotoxicity. 

Intermediate-Duration Exposure. Limited data are available regarding guthion-induced effects on 

ChE activity following repeated oral exposure of volunteers for 4 weeks (Rider and Puletti 1969; Rider et 

al. 1970, 1971, 1972). There was no effect on erythrocyte AChE or plasma ChE activity at the doses 

tested. No intermediate-duration inhalation or dermal studies were located regarding guthion toxicity in 

humans. No intermediate-duration dermal studies were located regarding guthion toxicity in animals; 

however, the effects elicited by exposure to guthion are not expected to be route-dependent and the 

effects from dermal exposure are expected to be similar to those observed after oral or inhalation 

exposure. Intermediate-duration studies have evaluated the neurotoxic, systemic, reproductive, and 

developmental effects of guthion administered orally or by inhalation to rats and dogs (Allen et al. 1990; 

Holzum 1990; Kimmerle 1976; Schmidt and Chevalier 1984; Sheets et al. 1997; Short et al. 1980; Vos et 

al. 1983). A number of studies have demonstrated that neurotoxicity, exhibited as significant reductions 

in erythrocyte AChE or clinical signs of neurotoxicity, is the most sensitive end point following 

intermediate-duration exposures to guthion. Increased mortality was observed in rats administered 

guthion by gavage (Short et al. 1980) or in the diet (Holzum 1990). The available experimental data 

suggest that developmental and reproductive effects are evident mostly at doses that are maternally toxic 

or that elicit significant reductions in parental erythrocyte AChE. ATSDR derived an intermediate­
GUTHION 93 

3. HEALTH EFFECTS 

duration inhalation MRL based on the study by Kimmerle (1976) and an intermediate-duration oral MRL 

based on the study by Allen et al. (1990). 

Chronic-Duration Exposure and Cancer. No controlled studies were located regarding guthioninduced toxicity following chronic-duration inhalation or dermal exposure of humans or animals. No 

studies of chronic, oral exposure to guthion in humans were located. Information from chronic toxicity 

studies is important because people working with guthion might be exposed to this pesticide for many 

years. The study by Weinbaum et al. (1997) suggests that dermal, and perhaps inhalation, exposures of 

workers to guthion may lead to adverse health effects. An increased association was observed between 

the occurrence of systemic illness (defined as an acute illness following pesticide exposure, with 

symptoms and signs not restricted to the eyes or skin) in workers and agricultural use of guthion 

(Weinbaum et al. 1997). Chronic-duration studies in dogs and rats have evaluated the systemic and 

neurological effects of guthion administered in the diet for up to 2 years (Allen et al. 1990; Schmidt and 

Chevalier 1984). ATSDR derived a chronic-duration inhalation MRL based on Kimmerle (1976) and a 

chronic-duration oral MRL based on Allen et al. (1990). A study of the long-term neurological effects of 

exposure to guthion is warranted. 

No studies were located regarding cancer in humans following oral exposure to guthion. A 2-year 

carcinogenicity study in rats and mice showed an increased combined incidence of islet cell carcinoma or 

carcinomas of the pancreas in male rats exposed to 10.9 mg/kg/day guthion in the diet for 80 weeks 

followed by a 35-week observation period (NCI 1978). However, this lesion occurs at a high spontaneous 

incidence in the animals used in this study and the increased incidence in the treated males could not be 

unequivocally attributed to treatment with guthion (NCI 1978). Similarly, the increases in the incidence 

of benign thyroid tumors, malignant thyroid tumors, or combined follicular cell tumors observed in male 

rats exposed to 5.5 or 10.9 mg/kg/day (NCI 1978) could not be attributed to treatment with guthion due to 

the historically high spontaneous incidence of these neoplasms in male rats in this laboratory (NCI 1978). 

There was no evidence of the occurrence of treatment-related tumors in female rats in this study or in 

another study of male and female Wistar rats exposed to 0.25–3.11 mg/kg/day for 2 years (Schmidt and 

Chevalier 1984). Benign and malignant neoplasms were observed among dosed and control 

B6C3F1 mice, but these lesions appear to occur spontaneously in mice in this laboratory and the effect 

could not be attributed to guthion (NCI 1978). The incidences of neoplasms of the pancreatic islets and 

of the follicular cells of the thyroid in male rats provide suggestive but insufficient evidence of a 

carcinogenic potential of guthion in male rats (NCI 1978). There was no significant increase in the 

incidence of tumors in female rats. The results of these studies led NCI (1978) to conclude that, under the 
GUTHION 94 

3. HEALTH EFFECTS 

conditions of this bioassay, guthion was not carcinogenic in male or female mice or female rats. There 

was suggestive but insufficient evidence to conclude that guthion was carcinogenic in male rats. 

Additional carcinogenicity studies with guthion are not needed at this time. 

Genotoxicity. No in vivo studies of genotoxic effects in humans were located. Six of the 11 in vitro 

studies with eukaryotic organisms (fungi and mammalian cells) that were located showed positive results 

for genotoxic effects (Alam and Kasatiya 1976; Alam et al. 1974; Bianchi–Santamaria et al. 1997; Hrelia 

et al. 1990; Waters et al. 1982; Zeiger et al. 1987), but the remaining studies (Carere et al. 1978; Hrelia et 

al. 1990; Waters et al. 1982) did not. An in vivo genotoxicity evaluation of persons exposed to guthion, 

particularly agricultural workers, would provide data that could assist in establishing the genotoxic 

potential of this insecticide in humans. 

Reproductive Toxicity. No studies are available on the reproductive toxicity of guthion in humans 

through any route of exposure or in animals exposed dermally or by inhalation. The reproductive toxicity 

of guthion has been evaluated in mice and rats administered guthion orally. Reductions in the incidence 

of viable litters were observed in the offspring of pregnant mice administered 20 mg/kg guthion orally 

once on gestation day 8 (Kavlock et al. 1985). Astroff and Young (1998) did not observe reproductive 

effects in pregnant rats administered guthion at 2 mg/kg/day on gestation days 6–15. Insemination, 

fertility, or gestation indices or duration of gestation were not affected in male and female rats 

administered guthion at 0.43 to 4.9 mg/kg/day in the diet for 14 weeks before mating and continuously 

through gestation (Holzum 1990). The available evidence suggests that adverse reproductive effects are 

observed at doses that are higher than doses eliciting maternal toxicity. Thus, an additional study of the 

reproductive toxicity of guthion in animals after intermediate-duration exposure is not needed at this time. 

Developmental Toxicity. No controlled studies are available on the developmental toxicity of 

guthion in humans by any route of exposure. No association was observed between occupational 

exposure to guthion and the occurrence of congenital malformations in a study of male agricultural 

workers conducted in Spain during 1993 and 1994 (García et al. 1998). Increased incidences of 

supernumerary ribs and reduced fetal body weight gain were observed in the offspring of pregnant mice 

administered a single oral dose of guthion at 16 and 20 mg/kg, respectively (Kavlock et al. 1985). 

Increased incidences of malaligned sternbrae and reduced body weight gain, brain weight, brain AChE 

activity, and survival were observed in the pups of pregnant rats administered 1.3–5 mg/kg/day during 

gestation (Holzum 1990; Short et al. 1980). The available experimental data suggest that in most studies 

developmental effects are evident only at doses that are maternally toxic. Thus, additional studies of the 
GUTHION 95 

3. HEALTH EFFECTS 

in utero developmental toxicity of guthion do not seem necessary at this time; however, information is 

lacking regarding the developmental effects of exposures of juvenile animals or children to guthion and a 

study to fill this data gap is warranted. 

Immunotoxicity. No studies were located on the immune toxicity in humans exposed to guthion by 

inhalation or oral exposure. Two studies examined the incidence of allergic responses in volunteers who 

were administered skin patches. In one of these studies guthion did not elicit a dermal immune response 

(Lisi et al. 1987), while in the other study, 1 of 63 workers showed an allergic reaction to guthion 

(Sartorelli et al. 1999). Vos et al. (1983) reported decreased relative spleen and mesenteric lymph node 

weights, as well as unspecified histopathologic findings in the thymus in male Wistar rats exposed to 

guthion in the diet at 11.5 mg/kg/day for 3 weeks. An increase in mortality was also observed at 

11.5 mg/kg/day; no effects were observed at 2.3 mg/kg/day (Vos et al. 1983). Thymus and spleen 

morphology were not affected in rats exposed to guthion by inhalation for up to 12 weeks (Kimmerle 

1976). The available evidence suggests that guthion elicits an unspecified immune response only at levels 

that also increase mortality. Thus, additional immunotoxicity studies are not warranted at this time. 

Neurotoxicity. Available studies strongly suggest that adverse effects on the nervous system are the 

most sensitive end points of guthion toxicity and these effects are well characterized. Although no 

significant changes in plasma ChEor erythrocyte AChE activity were observed in a small group of 

subjects who took guthion orally at 0.057–0.086 mg/kg/day for 4 weeks (Rider and Puletti 1969; Rider et 

al. 1970, 1971, 1972), studies of agricultural workers have demonstrated 10–20% reductions in 

erythrocyte AChE or whole blood ChE activity after a single air-blast application of guthion (Franklin et 

al. 1981) or after entering field treated with guthion (Kraus et al. 1977; McCurdy et al. 1994; Schneider et 

al. 1994). Despite the reductions in erythrocyte AChE activity, workers did not exhibit clinical signs of 

neurotoxicity. A number of animal studies have demonstrated marked reductions in erythrocyte, brain, or 

plasma AChE activity, or whole blood ChE activity as well as clinical signs of neurotoxicity after acute-, 

intermediate-, or chronic-duration exposures to guthion by inhalation (Kimmerle 1976), oral (Allen et al. 

1990; Astroff and Young 1998; EPA 1978a; Holzum 1990; Pasquet et al. 1976; Schmidt and Chevalier 

1984; Sheets et al. 1997; Short et al. 1980; Su et al. 1971), or dermal (EPA 1978a; Skinner and Kilgore 

1982) exposure routes. No data are currently available to address the possibility of long-term 

neurological effects of repeated exposure to guthion. Thus, it is recommended that a battery of tests 

designed to detect subtle neurological effects be conducted among workers involved in the application of 

guthion or who enter fields treated with guthion. 
GUTHION 96 

3. HEALTH EFFECTS 

Epidemiological and Human Dosimetry Studies. Agricultural workers face the highest risk of 

exposure to guthion. Studies of agricultural workers who applied guthion (Franklin et al. 1981) or 

entered fields treated with guthion (Kraus et al. 1977; McCurdy et al. 1994; Schneider et al. 1994) showed 

reductions in erythrocyte AChE activity or whole blood ChE activity, but did not exhibit clinical signs of 

neurotoxicity. These studies have examined changes in erythrocyte AChE activity over brief exposure 

durations and have generally not addressed systemic effects. Thus, an epidemiological study of 

agricultural workers exposed chronically to guthion would help evaluate the suggested association 

between the incidence of systemic illness and agricultural use of guthion (Weinbaum et al. 1997). An 

accurate quantification of exposure to guthion would be necessary to derive useful data from such a study. 

Biomarkers of Exposure and Effect. 

Exposure. The ideal biomarker for the quantification of exposure to guthion would be specific to the 

chemical of interest and would probably be the insecticide itself or a metabolite that could only be 

detected after exposure to guthion. It has been shown that DMPDT, DMTP, and DMP are metabolic 

products of the in vivo degradation of guthion (Carrier and Brunet 1999) and have been detected in urine 

of humans exposed to guthion under field and experimental conditions (Aprea et al. 1994; Franklin et al. 

1986); however, these metabolites are not specific to guthion, but indicate potential exposure to a variety 

of organophosphate pesticides. Direct monitoring data of guthion in humans is rare since its biological 

half-life is short. No studies were located that detected guthion or gutoxon in blood of exposed animals 

or humans. Reductions in plasma ChE and erythrocyte AChE activity and clinical symptoms of 

neurotoxicity are reliable biomarkers of exposure to guthion; however, it is currently not possible to use 

these biomarkers to distinguish between exposure to guthion and other organophosphorus insecticides. 

Development of a biomarker of exposure specific to guthion would be useful in conducting exposure 

assessments and epidemiological studies. 

Effect. Cholinergic symptoms of neurotoxicity and reductions in erythrocyte AChE activity (a surrogate 

for nervous system AChE activity) provide reliable biomarkers for the effect of guthion; however, these 

effects are not unique to guthion exposure and are elicited by other organophosphate and carbmamate 

ester insecticides as well. In addition, the large degree of variability in ChE activity in human populations 

suggests that caution should be exercised when comparing ChE activities from exposed populations, such 

as agricultural workers, and reference populations (Coye et al. 1987; Maroni et al. 2000). Development 

of a biomarker of effect specific to guthion would be useful in conducting exposure assessments and 

epidemiological studies. 
GUTHION 97 

3. HEALTH EFFECTS 

Absorption, Distribution, Metabolism, and Excretion. Animal studies have demonstrated that 

guthion is absorbed via the inhalation pathway, as can be inferred from the observed reductions in 

erythrocyte AChE activity (Kimmerle 1976) and whole blood ChE activity (EPA 1978a) following acuteor intermediate-duration exposure. No human data are available from which to estimate the absorption of 

guthion after oral exposure, but animal studies suggest that guthion is rapidly absorbed after oral exposure 

(Fakhr et al. 1996). The detection of urinary metabolites of guthion in dermally-exposed humans and rats 

serves as indication that dermally applied guthion is absorbed (Feldmann and Maibach 1974; Franklin et 

al. 1983). 

No studies are available regarding the distribution of guthion in exposed humans or animals following 

inhalation exposure; however, the distribution of guthion in exposed animals or humans is not expected to 

be route-dependent. A study on the distribution of guthion administered orally to rats was located (Fakhr 

et al. 1996). The bioactivation of guthion to gutoxon and the detoxication of guthion is understood 

(Dahm et al. 1962; Hitchcock and Murphy 1971; Levine and Murphy 1977; Motoyama and Dauterman 

1972; Sultatos and Woods 1988). Studies suggest that the role of different cytochromes in the 

bioactivation process may be dependent on the guthion concentration (Buratti et al. 2003). 

Urinary excretion of guthion metabolites has been demonstrated in humans (Aprea et al. 1994); however, 

the detected metabolites are not unique to guthion. No information was located on the elimination and 

excretion of guthion in human or animals following inhalation exposure. Elimination of guthion is not 

expected to be route dependent. Radiolabeled guthion metabolites were eliminated largely in expired air, 

and feces of rats after a single oral dose; neither guthion nor its oxon metabolite were detected by 

chromatographic analysis of the urine (Fakhr et al. 1996). Urinary excretion of radiolabeled metabolites 

of guthion (predominantly DMTP) has been examined in dermally exposed human subjects (Feldmann 

and Maibach 1974; Franklin et al. 1986) and laboratory animals (Franklin et al. 1983). The urinary output 

of radiolabeled guthion metabolites after an intramuscular injection to rats showed two peaks in urinary 

excretion of the administered dose, one 4 hours after the dose (approximately 13% of the dose) and a 

higher peak (approximately 20% of the dose) after 24 hours, which was followed by a rapid decrease in 

output (Franklin et al. 1983). Urinary recovery of metabolites observed in a study with human subjects 

administered a single intravenous dose of radiolabeled guthion also showed an initial peak (1.5% 

dose/hour) 0–4 hours after the dose was administered, which was followed by a drop in excretion and a 

second peak (1.6% dose/hour) 812 hours after the dose was administered (Feldmann and Maibach 1974). 
GUTHION 98 

3. HEALTH EFFECTS 

The pharmacokinetics of guthion are fairly well understood; additional pharmacokinetic studies are not 

considered necessary at this time. 

Comparative Toxicokinetics. No studies were located that directly evaluated the comparative 

toxicokinetics of guthion in animals and humans. Nevertheless, available studies suggest that the 

toxicokinetics of guthion in animals and humans are generally similar (EPA 1999b; Feldmann and 

Maibach 1974, Zendzian 2003) and that neural AChE is the critical target of guthion toxicity in animals 

and humans (Buratti et al. 2003; Hitchcock and Murphy 1971). Recent work suggests that the 

desulfuration of guthion to gutoxon in human liver microsomes is largely effected by at least three 

cytochromes (CYP1A2, CYP3A4, and CYP2B6), which show different affinities for the substrate (Buratti 

et al. 2003). If the spectrum of activities of these cytochromes in animals varies markedly from that in 

humans, notable differences in animals and humans might be expected. No data are available to 

determine whether such differences exist. A study of the comparative toxicokinetics of guthion in 

animals and humans may be warranted. 

Methods for Reducing Toxic Effects. Guthion exerts its systemic effects through inhibition of 

AChE in the central and peripheral nervous systems. Guthion is bioactivated in vivo and in vitro to its 

oxygen analog form, gutoxon (Buratti et al. 2003; Hitchcock and Murphy 1971; Sultatos and Woods 

1988), which reacts with a serine hydroxyl group at the active site of AChE, rendering it largely inhibited 

and unreactive. The inhibited AChE enzyme cannot degrade acetylcholine and the neurotransmitter 

accumulates at the ending of cholinergic nerves with the ensuing continual stimulation of electrical 

activity (Carrier and Brunet 1999). Intoxications with guthion are managed as are intoxications caused by 

other organophosphate insecticides, namely, by administering respiratory support, atropine treatment, and 

reactivation of neural AChE with 2-PAM (Carlton et al. 1998; Tafuri and Roberts 1987). The mechanism 

of inhalation, oral, or dermal absorption of guthion is not known. Research is needed to develop an 

understanding of the mechanisms of route-specific absorption of guthion. Currently, no methods exist to 

promote the excretion of guthion or its active metabolite, gutoxon. Research is needed to develop 

methods to promote the excretion of guthion and the active metabolite gutoxon. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 
GUTHION 99 

3. HEALTH EFFECTS 

No information is available for any route of exposure regarding potential age-related differences in 

guthion toxicity in humans or animals. No cases of children poisoned by exposure to guthion were 

located. Nevertheless, the critical targets of guthion toxicity can be expected to be similar in children and 

adults. Comparative studies of the toxicity and toxicokinetics of guthion in juvenile and adult animals are 

needed. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

One ongoing study pertaining to the health effects of guthion has been identified in the Federal Research 

in Progress (FEDRIP) database. J.E. Chambers, J.S. Boone, and R.L. Carr of the College of Veterinary 

Medicine at Mississippi State University are conducting an investigation of the biochemical and 

physiological factors contributing to the age-related differences in responses of mammals to insecticides 

(FEDRIP 2006). 
GUTHION 100 

3. HEALTH EFFECTS 

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GUTHION 101 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of guthion is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Guthion is a nonsystemic organophosphate insecticide. Pure guthion is a colorless to white, odorless, 

crystalline solid with a melting point range of 72–74 °C, while the technical-grade material is a cream to 

yellow-brown, granular solid with a melting point of 67–70 °C (EPA 2001b). Guthion is readily soluble 

in most organic solvents (acetone, toluene, chloroform, acetonitrile, benzene, xylene, carbon tetrachloride, 

and chlorobenzene), slightly soluble in methanol, ethanol, and propanol, and poorly soluble in water. 

Information regarding the physical and chemical properties of this compound is located in Table 4-2. 
GUTHION 102 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Guthion 

Characteristics Guthion References 

Chemical name S-(3,4-Dihydro-4-oxobenzo[d]-[1,2,3]-triazin-3-yl- Tomlin 2003 

methyl)O,O-dimethylphosphorodithioate 

Synonyms O,O-Dimethyl S-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)­ Tomlin 2003 

methyl]; Azinphos-methyl 

Trade names Guthion; Aziflo; Azin-PB; Crysthyon; Mezyl; Sniper; Tomlin 2003 

Supervalex 

Chemical formula C10H12N3O3PS2 Tomlin 2003 

Chemical structure Tomlin 2003 

O CH3 

CH3 

Identification numbers: 

CAS registry 86-50-0 Tomlin 2003 

 NIOSH RTECS TE1925000 NIOSH 2005 

EPA hazardous waste No data 

 OHM/TADS No data 

 DOT/UN/NA/IMCO shipping NA 2783; Guthion mixture, liquid HSDB 2008 

HSDB 1171 HSDB 2008 

NCI No data 

N 

N 

N 

O 

S 

P 

S 

O 
GUTHION 103 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Guthion 

Property Information References 

Molecular weight 317.3 Tomlin 2003 

Color Colorless to white (pure material); cream to 

yellow brown (technical grade material) 

EPA 2001b 

Physical state Crystalline Tomlin 2003 

Melting point 72–74 °C (pure material); 67–70 °C 

(technical-grade material) 

EPA 2001b 

Boiling point Decomposes above 200 °C Tomlin 2003 

Specific gravity (20 °C) 1.518 Tomlin 2003 

Odor Odorless EPA 2001b 

Odor threshold 

 Water 0.0002 mg/kg Verschueren 2001 

Air No data 

Solubility 

Water at 25 °C 28 mg/L Tomlin 2003 

Organic solvents >250 g/L in dichloroethane, acetone, 

acetonitrile, ethyl acetate, and DMSO; 

1.2 g/L in n-heptane and 170 g/L in xylene 

(all at 20 °C) 

Tomlin 2003 

Partition coefficients 

 Log Kow 2.75 Hansch et al. 1995 

 Log Koc 2.69–3.67 Gawlik et al. 1998 

Vapor pressure 

 20 °C 

Henry’s law constant 

3x10-5 Pa (2.2x10-7 mm Hg) 

3.7x10-9 atm-m3

/mol 

Suntio et al. 1988 

EPA 1999a 

Flashpoint (closed cup) No data 

Flammability limits 

Air No data 

Conversion factorsa 

ppm (v/v to mg/m3

 in air (20 °C) 

mg/m3

 to ppm (v/v) in air (20 °C) 

1 ppm = 13.2 mg/m3

1 mg/m3 = 0.076 ppm 

 Verschueren 2001 

Verschueren 2001 

Explosive limits No data 

a

Guthion exists partially in the particulate-phase in the atmosphere. This conversion is only applicable to vaporphase guthion. 
GUTHION 104 

4. CHEMICAL AND PHYSICAL INFORMATION 

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GUTHION 105 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

Guthion is produced by the reaction of N-bromethylazimidobenzoyl with sodium dimethyldithiophosphoric acid (NRC 1977). Current production volumes are not known. In 1997, 2,091,014 pounds of 

guthion were used on crops throughout the United States with the vast majority being applied to apple 

orchards (USDA 2000). This represented an 18% decrease from national usage data compiled for 1992 in 

which 2,548,867 pounds were used. In the Interim Registration Eligibility Decision (interim RED) 

document for guthion, EPA estimated that <2 million pounds are used annually (EPA 2001b). Current 

use volumes of guthion throughout the United States are expected to be considerably lower than in 

previous years since many of the registered uses for this insecticide have been cancelled or are expected 

to be cancelled in upcoming years (see Section 5.3). For example, according to the State of California 

Department of Pesticide Regulation, use of guthion has decreased in California from over 400,000 pounds 

in 1994, to slightly over 50,000 pounds used in 2004 (CDPR 2006). The SRI Directory of Chemical 

Producers lists Bayer Crop Science as the only manufacturer of guthion in 2005 (SRI 2005); however, 

according to the National Pesticide Information Retrieval System, there are currently four active 

registrants manufacturing formulated products or technical-grade guthion (NPIRS 2006). These 

companies and the products produced are described in Table 5-1. 

No information is available in the TRI database on facilities that manufacture or process guthion because 

this chemical is not required to be reported under Section 313 of the Emergency Planning and Community 

Right-to-Know Act (Title III of the Superfund Amendments and Reauthorization Act of 1986) (EPA 

1998c). 

5.2 IMPORT/EXPORT 

No current data are available regarding the volume of guthion imported or exported to and from the 

United States. As with many pesticides with production or uses involving proprietary information, 

quantitative estimates of production, import, and export volumes are not publicly available (Bason and 

Colborn 1992). 
GUTHION 106 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Manufacturers of Technical-Grade or Formulated Products 

Containing Guthion 

Number of 

Company name and address active products Product description(s) 

Bayer CropScience 2 

Research Triangle Park, North Carolina 27709 

(919)549-2000 

Gowan Company 5 

Yuma, Arizona 85366-5569 

(928)783-8844 

Makhteshim Chemical Works, Ltd. 1 

Makhteshim-Agan of North America, Inc. 

Raleigh, North Carolina 27609 

(919)256-9300 

Micro-Flo Company, LLC 3 

Memphis, Tennessee 38117 

(901)432-5118 

Source: NPIRS 2006 

Technical-grade powder and 

50% wettable powder 

Technical-grade powder, 50% water 

soluble bags, 35% water soluble 

bags, 35% wettable powder, and 

50% polyvinyl acetate bags 

Technical-grade powder 

35% Emulsifiable concentrate, 

35% wettable powder, 50% wettable 

powder 
GUTHION 107 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.3 USE 

Guthion is a broad spectrum organophosphate insecticide, acaricide, and molluscacide that has been used 

to control a wide variety of insects including codling moths, plum curculios, apple maggots, aphids, 

leafrollers, mites, mealybugs, moths, and boll weevils (EPA 2001b). It has been used on a variety of 

crops; however, its major use has been on tree crops, including pome and stone fruit and nut crops (EPA 

2001b). 

In 2001, the EPA published its interim RED for guthion, in which it concluded that all uses of guthion 

were ineligible for re-registration based on their currently approved labeling (EPA 2001b). The EPA 

proposed the immediate cancellation of 28 Group 1 uses of guthion (alfalfa, beans—succulent or snap, 

birdsfoot trefoil, broccoli, cabbage including Chinese, caneberries—foliar application only, cauliflower, 

citrus, celery, clover, cucumbers, eggplants, filberts, grapes, melons, nectarines, nursery stock other than 

quarantine use, onions—green, onions—dry bulb, parsley, pecans, peppers, plums and dried plums, 

potatoes, quince, spinach, strawberries, and tomatoes), which were deemed to have little use and/or low 

benefits. Another seven uses were allowed to continue with a 4-year phase out since these uses were 

considered to have moderately high economic benefit. The remaining uses were considered to have 

significant economic benefits for which no adequate pesticide could be used in place of guthion 

(California EPA 2004). These uses were considered eligible for re-registration with 4-year time limited 

tolerances. If no request was made for re-registration these uses were set to expire in October 2005. In 

July 2004, the guthion registrants submitted applications to extend the registrations for the remaining 

10 uses of guthion (Group 3 uses). These uses include almonds; apples/crabapples; blueberries, lowbush 

and highbush; Brussels sprouts; cherries, sweet and tart; nursery stock; parsley; pears; pistachios; and 

walnuts. On March 29, 2006, EPA amended the registrations of guthion products to terminate the Group 

2 uses, which include caneberries, cotton, cranberries, peaches/nectarines, potatoes, and Southern pine 

seed orchards (EPA 2006j). This order follows up on an August 2005 notice of receipt of requests from 

the registrants to voluntarily cancel the Group 2 uses. Under the existing stocks provisions, distribution 

or sale of these products for these uses is allowed until March 31, 2006, and use of these products is 

allowed until September 30, 2006. On June 9, 2006, EPA proposed the cancellation of guthion usage for 

apples, blueberries, cherries, parsley, and pears by 2010 and cancellation of its uses on almonds, Brussels 

sprouts, pistachios, walnuts, and nursery stock by 2007 (EPA 2006l). 
GUTHION 108 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.4 DISPOSAL 

The two methods most frequently employed for the disposal of organophosphate pesticides such as 

guthion are incineration and alkaline hydrolysis (NIOSH 1981). Incineration involves dissolving guthion 

in a flammable solvent such as alcohol followed by atomization in a suitable combustion chamber 

equipped with an appropriate effluent gas cleaning device. 

Guthion is listed as toxic substances under Section 313 of the Emergency Planning and Community Right 

to Know Act (EPCRA). Disposal of wastes containing these compounds is controlled by a number of 

federal regulations (see Chapter 8). The EPA Office of Pesticide Programs has detailed labels for the use, 

storage, and disposal of all pesticides, including registered products containing guthion. All pesticide 

products are required to bear instructions for the storage and disposal of the pesticides and the pesticide 

containers. Storage and disposal instructions cover the appropriate storage of the pesticide product; 

disposal of any unused pesticide product or any rinse liquids resulting from cleaning of pesticide 

application equipment; and the disposal of the pesticide container. State and local regulations may be 

stricter than the federal requirements listed on the label. 
GUTHION 109 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Guthion has been identified in at least 5 of the 1,699 hazardous waste sites that have been proposed for 

inclusion on the EPA National Priorities List (NPL) (HazDat 2008). However, the number of sites 

evaluated for guthion is not known. The frequency of these sites can be seen in Figure 6-1. 

Guthion is a restricted use organophosphate insecticide that is primarily used as a foliar application 

against phytophagous insect pests on fruit, field, or vegetable crops and works as both a contact 

insecticide and a stomach poison. In 2001, the EPA proposed the immediate cancellation of most uses of 

guthion. The only crops that guthion can still be applied to are almonds; apples/crabapples; blueberries, 

lowbush and highbush; Brussels sprouts; cherries, sweet and tart; nursery stock; parsley; pears; 

pistachios; and walnuts. On August 8, 2007, the companies that produce guthion voluntarily requested to 

amend their registrations which would effectively terminate certain uses (Brussels sprouts and nursery 

stock) of guthion by September 30, 2007 (EPA 2007). Uses on walnuts, almonds, and pistachios are 

scheduled to cease by October 30, 2009, and all other uses would be terminated by September 30, 2012 

(EPA 2007). The application rate of guthion varies depending upon which crop it is applied to, but is 

typically in the range of 0.3–1.4 pounds a.i./A (EPA 1999a). 

Guthion is not considered highly persistent in the environment, and degrades by a combination of biotic 

and abiotic mechanisms. Biodegradation occurs readily in soils and water under aerobic conditions with 

half-lives on the order of several days to a few weeks. Hydrolysis and photolysis are also important 

degradation pathways for guthion in water, foliage, and soils. In the atmosphere, vapor-phase guthion is 

quickly degraded by photochemically produced hydroxyl radicals; the half-life for this reaction in air is 

on the order of a few hours. Particulate-phase guthion is removed from the atmosphere by wet and dry 

deposition processes. Guthion has moderate to low mobility in soils. Its leaching potential is considered 

low, and therefore, guthion is only occasionally detected in groundwater. 

Levels of guthion in the environment can vary considerably. In areas where it is not used, it is rarely 

detected, suggesting that long-range transport of this chemical does not occur. However, guthion is 

frequently detected in surface water bodies near fields or orchards where it has been applied as an 

insecticide. The most important route of exposure to guthion for the general population is through the 

ingestion of foods, especially vegetables and fruits that have been sprayed with this insecticide. Ingestion 

of contaminated drinking water, inhalation exposure, and dermal exposure to guthion are expected to be 
GUTHION 110 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Guthion Contamination 
GUTHION 111 

6. POTENTIAL FOR HUMAN EXPOSURE 

low for the general population. Agricultural workers, their families, and persons residing near crops that 

are treated with guthion are expected to have much greater frequency of exposure and the potential to be 

exposed to higher levels of guthion than the general population. 

6.2 RELEASES TO THE ENVIRONMENT 

The amount of guthion used in the United States, and thus released to the environment, appears to be 

declining. The total amount of guthion used in 1997 was reported as 2,091,014 pounds, which was an 

18% decrease from the amount used (2,548,867 pounds) in 1992 (USDA 2000). In 2002, the estimated 

annual agricultural use of guthion had declined to about 1.2 million pounds, nearly a 50% decline from 

1997 (USGS 2007). Recent restrictions on the crops that guthion can be applied to are likely to result in 

lower emissions in future years. 

There is no information on releases of guthion to the environment from manufacturing and processing 

facilities because these releases are not required to be reported (EPA 1998c). 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

6.2.1 Air 

There is no information on releases of guthion to the atmosphere from manufacturing and processing 

facilities because these releases are not required to be reported (EPA 1998c). 
GUTHION 112 

6. POTENTIAL FOR HUMAN EXPOSURE 

Guthion releases to the atmosphere arise from its use as an insecticide where it is applied to crops by 

aerial application or with ground-based boom sprayers. Guthion was detected in air samples at one of the 

five current or former NPL hazardous waste sites where it was detected in some environmental media 

(HazDat 2008). 

6.2.2 Water 

There is no information on releases of guthion to the water from manufacturing and processing facilities 

because these releases are not required to be reported (EPA 1998c). 

Guthion is released to water from point source discharges, spray drift from aerial applications, and runoff 

and erosion of treated soils. A multi-year study from 1981 to 1984 was conducted to determine the 

loadings of carbofuran, fenvalerate, and guthion to Lake Oconee in Georgia from the treatment of a pine 

seed orchard adjacent to the lake (Bush et al. 1986). A series of approximately 85 rainfall events over a 

49 month period produced varying amounts of runoff and erosion loadings into the lake. For example, 

guthion was applied aerially in April of 1981 and a rainfall event 10 days postapplication produced 

1,540 μg/L of guthion in the resultant runoff water (Bush et al. 1986). The amount of spray drift entering 

the lake was estimated by placing a series of 9 glass fiber disks within the treatment zone of the orchard 

and 12 discs along the edge of the lake. The discs within the treatment zone averaged 1,201 μg of guthion 

per disc, while the discs adjacent to the lake averaged 1.2 μg of guthion per disc (Bush et al. 1986). 

Two field runoff studies were submitted by the Bayer Corporation to the EPA in support of the 

registration of guthion (EPA 1999a). These two studies were conducted on cotton fields in Colquitt 

County, Georgia and Benoit, Mississippi. A single application of guthion at an application rate of 

0.25 pounds a.i./A was made in August 1989 to the Mississippi field. Eight applications of guthion 

(0.25 pounds a.i./A) were made at 3-day intervals starting on August 1 at the Georgia location. At the 

Mississippi site, a total of 14.9 g of guthion was released in runoff from the 5.2-acre plot during a heavy 

rainfall event that produced 3.08 inches of precipitation 2 days postapplication. Approximately 31.5% of 

the precipitation was accounted for in runoff from the plot during the rainfall event (EPA 1999a). A total 

of 13.3 g of guthion was released in runoff from the 9-acre portion of the Georgia field in four storms 

which occurred on August 8 (32 mm of precipitation), August 26 (61 mm of precipitation), August 

31 (37 mm of precipitation), and October 1 (33 mm of precipitation). These produced 3.6, 8.3, 1.3, and 

0.0012 g of guthion in the collected runoff, respectively (EPA 1999a). 
GUTHION 113 

6. POTENTIAL FOR HUMAN EXPOSURE 

Guthion was detected in the groundwater at one of the five current or former NPL hazardous waste sites 

where it was detected in some environmental media (HazDat 2008). There were no detections of guthion 

in surface water at any of these sites. 

6.2.3 Soil 

There is no information on releases of guthion to the soil from manufacturing and processing facilities 

because these releases are not required to be reported (EPA 1998c). 

Guthion is released directly to soils from its registered use as an insecticide (EPA 1999a). Deposition to 

the ground following aerial spraying or direct applications via chemigation or sprinkler irrigation systems 

is common. Guthion was detected in soil samples at three of the five current or former NPL hazardous 

waste sites where it was detected in some environmental media (HazDat 2008). There were no detections 

of guthion in sediment at any of these sites. 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

The vapor pressure of guthion is 2.2x10-7 mm Hg (Suntio et al. 1988) and its estimated Henry’s law 

constant is 3.7x10-9 atm-m3

/mol, calculated from its vapor pressure and water solubility (EPA 1999a). 

These values suggest that guthion is essentially nonvolatile from water and soil surfaces. The 

volatilization flux of guthion from treated walnut orchards was estimated using the EPA’s 

SCREEN-2 dispersion model (Woodrow et al. 1997). The estimated volatilization flux from the surface 

of the walnut tree leaves was 0.067 μg/m2

-second, which resulted in an estimated atmospheric 

concentration of approximately 0.23 μg/m3

 15 m downwind from the application site. 

In the atmosphere, postapplication spray drift is an important source of environmental contamination and 

is responsible for much of guthion’s transport outside of its target zone. The amount of spray drift is 

influenced by meteorological conditions such as wind speed and method of application (e.g., aerial or 

ground spraying). Droplet size, humidity, and temperature are also important factors that can affect spray 

drift. In general, fine droplet size, low humidity, and warm temperatures enhance the likelihood of 

increased spray drift. For most spray applications of pesticides, buffer zones are required between the 

target crop and any permanent water bodies. These buffer zones for guthion typically range from 25 feet 

for ground applications using boom sprayers to 150 feet for aerial applications to certain crops. Guthion 
GUTHION 114 

6. POTENTIAL FOR HUMAN EXPOSURE 

may be removed from the atmosphere by wet and dry deposition. This is confirmed by the detection of 

guthion in atmospheric rainwater samples (Section 6.4.1). The short atmospheric residence time of 

guthion suggests that it will not be transported long distances from its initial release point. 

Adsorption/desorption experiments using three different soils suggest that guthion has moderate to low 

mobility in soil and the potential to leach into groundwater is considered low. The Koc values of guthion 

in a sandy loam (1.6% organic carbon), silt loam (2.9% organic carbon), and clay loam (0.3% organic 

carbon) were calculated as 475, 579, and 3,266, respectively from the Freundlich adsorption coefficients 

(EPA 1999a). The adsorption characteristics of guthion in five standard European soils have also been 

studied (Gawlik et al. 1998). The Koc values in these five reference soils ranged from 534 to 4,644. The 

physical properties of these soils and corresponding adsorption coefficients are shown in Table 6-1. 

The mobility of guthion in soils under field conditions has been studied in two alfalfa fields located in 

California (EPA 1999a). In the first field, a single application of guthion was made to a portion of the 

field at 3 pounds a.i./A. In another section of the field, two applications of 3 pounds a.i./A were made 

7 days apart. The soil type of the field was described as Salinas silt that was slightly alkaline (pH 6.9– 

8.0). Over the course of 60 days, guthion was only detected in one soil sample below a depth of 6 inches, 

suggesting very limited mobility in the field. The same experimental protocol was employed in the 

second field located in Fresno, California. Guthion was not detected in any soil samples below a 

sampling depth of 6 inches in this field (EPA 1999a). Guthion was not detected below a depth of 30 cm 

when applied at an application rate of 9 pounds/A to a potato field with a soil texture that was described 

as a sandy loam and irrigated with 27.6 cm of water (Yaron et al. 1974). An aged soil column leaching 

study indicated that guthion and its degradation products are not particularly mobile in soils and the 

potential to leach into groundwater is low (EPA 1999a). Following application of an unspecified amount 

of 14C labeled guthion to a soil that was aged for 28 days and then dried before being packed into the 

column, 90% of the radioactivity was located in the top 5 cm of the column after application of 35.5 cm 

of water over 45 days. A total of 4.4% of the radioactivity leached from the bottom of the 30.5 cm 

column. 

The uptake and translocation of guthion in bean plants and barley has been demonstrated (Al-Adil et al. 

1973). The authors reported that guthion was readily absorbed through the roots and transported 

undegraded to other parts of the plant following incorporation into the soil or during direct application to 

the leaves. The assimilation of guthion by the roots and the translocation of the radiocarbon into the 

aerial parts of both plant species were most rapid during the first 24 hours. On day 8, the majority of the 
GUTHION 115 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Soil Adsorption Characteristics of Guthion in Five European Soils 

Orthic Podzol 

Vertic Cambisol Rendzina silt Dystric Cambisol Orthic Luvizol loamy sand 

Property (Italy) loam (Greece) loam (Wales) silt (France) (Germany) 

pH 5.1 7.4 5.2 6.5 3.2 

Percent 75% 22.6% 17% 20.3% 6% 

clay

Percent 1.3% 3.7% 3.45% 1.55% 9.25% 

organic 

carbon 

Kd 60.37 19.0 18.4 8.6 75.4 

1/na

 0.82 0.90 0.91 0.88 0.81 

Koc 4,644 487 534 556 815 

a

The parameter 1/n relates to the linearity of the adsorption isotherm. Generally, values close to 1 indicate a highly 

linear adsorption isotherm. 

Source: Gawlik et al. 1998 
GUTHION 116 

6. POTENTIAL FOR HUMAN EXPOSURE 

residues (98%) identified were of the undegraded parent compound. Topical application to the stem and 

seed injection with guthion also indicated translocation of the residues throughout the plant system. 

Based on its low mobility in soil, guthion is expected to adsorb to suspended solids and sediment in the 

water column. Guthion applied at a nominal application rate of 20 μg/L to the surface of a 2 ha pond was 

not detected in sediment samples 3 hours postapplication; however, guthion levels in sediment gradually 

increased to a maximum concentration of 62.7 μg/kg 4 days postapplication (Knuth et al. 2000). The 

levels gradually decreased to 11.9 μg/kg 8 days postapplication and then continued to decrease at a near 

constant rate to 2.05 μg/kg 50 days postapplication. Sediment samples collected at days 92, 120, and 

366 had no measurable levels of guthion (detection limits 0.20 μg/kg). Accounting for the total mass 

balance in the pond, the authors concluded that both the aqueous phase and the sediment compartment are 

important environmental sinks for guthion applied to the water surface. 

There are little data regarding guthion’s potential to bioconcentrate in aquatic organisms, and conflicting 

conclusions have been reported. According to an environmental fate and exposure assessment for guthion 

conducted by the EPA, bioconcentration and bioaccumulation are not expected based upon the log Kow 

value of guthion. An estimated bioconcentration factor (BCF) of 26 was calculated from a log Kow 

of 2.75 (Hansch et al. 1995) and a regression-derived equation (Meylan et al. 1999). This BCF value 

suggests that the potential for guthion to bioconcentrate and biocaccumulate in aquatic organisms is low. 

However, experimental studies using constructed ecosystems indicate that guthion may bioconcentrate in 

aquatic organisms. Guthion formulated as an emulsifiable concentrate and applied to the surface of a 

2-ha pond near Duluth, Minnesota at a nominal application rate of 20 μg/L showed accumulation in 

fathead minnows (Knuth et al. 2000). The level of dissolved guthion in the water column and the amount 

of guthion in adult fathead minnows were used to calculate lipid corrected BCF values. A maximum lipid 

corrected BCF value of 3,003 was observed 3 hours postapplication, while a minimum value of 1,027 was 

observed 1 day postapplication. Eight days postapplication, the BCF gradually increased to 2,254 (Knuth 

et al. 2000). Although these data indicate a high degree of bioconcentration, the whole-body BCF values 

in the minnows are substantially lower. Using the author-reported mean lipid content of 2.12% in the 

fathead minnows, the maximum whole-body BCF value is approximately 64 (3 hours postapplication), 

and the minimum value is approximately 22. These whole-body BCF values indicate that 

bioconcentration in aquatic organisms is low to moderate. These data are consistent with the findings of 

uptake and accumulation studies conducted using catfish. Catfish exposed to guthion had a relatively low 

magnitude of accumulation with rapid uptake and excretion (California EPA 2004). The accumulation 

factor was approximately 60 during the last 21 days of the 28-day exposure period. Guthion and the 
GUTHION 117 

6. POTENTIAL FOR HUMAN EXPOSURE 

desmethyl oxygen analog were observed in fish tissue. Approximately 67 and 85% of the residues were 

excreted within 5 hours and 4 days, respectively, after exposure was discontinued. 

6.3.2 Transformation and Degradation 

In general, guthion is not considered highly persistent in the environment. The dominant degradation 

mechanism in air is reaction with photochemically produced hydroxyl radicals and direct photolysis. In 

water, a combination of biodegradation, hydrolysis, and photolysis is expected to result in the degradation 

of guthion. Biodegradation appears to be the dominant degradation process for guthion in soils, and foliar 

degradation by photolysis is likely to limit the persistence of guthion on treated crops. 

6.3.2.1 Air 

Guthion has a vapor pressure of 2.2x10-7 mm Hg at 20 °C (Suntio et al. 1988), which suggests that it will 

exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase guthion is 

expected to be rapidly degraded through reaction with photochemically produced hydroxyl radicals and 

direct photolysis. An estimated hydroxyl radical rate constant of 1.5x10-10

 cm3/molec-second was 

estimated for guthion using a structure-estimation method (Meylan and Howard 1993). This corresponds 

to an atmospheric half-life of approximately 2.5 hours, assuming an atmospheric hydroxyl radical 

concentration of 5x105

 molec/cm3 (Atkinson 1985). In a direct photolysis study, thin films of guthion 

exposed to summer sunlight at Riverside, California degraded with an approximate half-life of 8.2 hours 

calculated using data by Chukwudebe et al. (1989). Three photodegradation products were observed 

including thiophosphoric acid O,S,O’-trimethyl ester, dithiophosphoric acid O,S,S'-trimethyl ester, and 

dithiophosphoric acid O,S,O'-trimethyl ester. 

6.3.2.2 Water 

Guthion is degraded through a combination of biotic and abiotic mechanisms in water, and is not 

considered persistent under environmental conditions. The hydrolysis half-lives of guthion at 30 °C in 

aqueous buffered solutions at pH 4, 7, and 9 were 49, 26, and 3.7 days, respectively (EPA 1999a). At 

40 °C the half-lives were 23, 13, and 1.8 days at pH 4, 7, and 9, respectively. A wide variety of 

metabolites were formed during these experiments and in general, initial concentration and temperature 

did not appear to affect the amount of each degradation product that was produced. Mercaptomethyl 

benzazimide was formed at 4.9–10.4% after 30 days at pH 7. Hydroxymethyl benzazimide and 

benzazimide, which were measured as a single analyte, were found after 30 days at 8.1–12.2% at pH 4, 
GUTHION 118 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.0–14.2% at pH 7, and 32.4–38.9% at pH 9. Anthranilic acid was also identified as a degradation 

product of guthion. Anthranilic acid was formed at 18.1–22.8% of the parent at 30 days in the pH 9 test 

systems. An unidentified metabolite was observed in the pH 9 test systems at 7.4–14.5% of the initially 

applied amount. Bismethyl benzazamide sulfide was also found at concentration <10% of the applied 

radioactivity. 

The aqueous photolysis half-life of guthion maintained at pH 4.35 and 30 °C and exposed to natural 

sunlight conditions in Kansas City, Missouri was calculated as 76.7 hours (EPA 1999a). Two major 

degradation products were identified, benzazimide and anthranilic acid. It was noted that each metabolite 

is actually a complex of two degradates that could not be separately identified by the analytical procedure 

used in the study. The benzazimide complex consisted of benzazimide and (1N)-methoxybenzazimide, 

while the anthranilic acid complex consisted of anthranilic acid and methyl anthranilate ester. 

Benzazimide complex represented 39.1% of the radiolabeled residues at the end of the experiment, while 

the anthranilic acid complex reached 7.2% of the radiolabeled residues at the end of experiment. 

An aerobic aquatic metabolism study was described that resulted in the formation of several degradation 

products of guthion; however, no rate data were supplied with this study (EPA 1999a). The degradation 

products identified were: des-methyl guthion, des-methyl guthion S-methyl isomer, methyl benzazimide, 

methylsulfinyl methyl benzazimide, methylsulfonyl methyl benzazimide, methyl benzazimide sulfonic 

acid, methylthiomethyl benzazimide, and either/or hydroxy-methyl benzazimide/benzazimide. The last 

two degradates were unresolved by the chromatographic method used for analysis. The only metabolite 

observed at >10% of the nominal concentration was methyl benzazimide sulfonic acid (EPA 1999a). 

The degradation kinetics of guthion in a mixture of 19 organophosphate and organonitrate pesticide 

solutions at the ppb level was measured in ultra-pure distilled water, natural seawater, river water, and 

filtered river water (Lartiges and Garrigues 1995). The experiments were conducted at two temperatures 

(6 and 22 °C), three pH levels (pH 6.1, 7.3, and 8.1), and in both the absence of light and under natural 

sunlight illumination in Bordeaux, France during the months of February to July. The experimental 

details and results are summarized in Table 6-2. In general, increasing pH led to greater degradation due 

to the base-catalyzed hydrolysis reaction of guthion; however, both hydrolysis and biodegradation appear 

to be attenuated at low temperatures. Degradation of guthion was enhanced considerably when the 

solutions were exposed to natural sunlight. Similar experimental results were obtained by Medina et al. 

(1999), using filtered and unfiltered water from the Limon River in Venezuela. The half-life of guthion 

was 23.5 days in filtered river water that was maintained under dark conditions and 13.4 days in filtered 
GUTHION 119 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Aqueous Degradation Rate of Guthion 

Half-life (days) 

pH 6 °C 22 °C Outdoor sunlighta 

MQW 6.1 415 115 No data 

River water 7.3 278 42 8 

Filtered river water 7.3 506 35 No data 

Seawater (salinity 25 g/L) 8.1 No degradation 26 11 

a

The temperatures under natural environmental conditions ranged from -2 to 25 °C. 

MQW = ultrapure water from a Millipore apparatus 

Source: Lartiges and Garrigues 1995 
GUTHION 120 

6. POTENTIAL FOR HUMAN EXPOSURE 

river water that was illuminated with natural sunlight. The half-life decreased to 6.1 days for nonfiltered 

river water exposed to sunlight during the course the experiments (Medina et al. 1999). 

The effect of chlorinating drinking water and the consequence that this has on organophosphate pesticides 

has been addressed (EPA 2002). Chemical oxidation of the thiophosphate group leads to the formation of 

guthion oxygenated metabolites (oxons), which were shown to be more stable than the parent compound 

in chlorinated systems. In water samples amended with sodium hypochlorite to yield a total chlorine 

residue level of 2 mg/L, guthion at a nominal concentration of 0.5 μg/L was transformed to its oxon, with 

a half-life of approximately 2 hours. After 24 additional hours, only 10% degradation of the oxon was 

observed. 

6.3.2.3 Sediment and Soil 

Guthion undergoes biodegradation, photolysis, and hydrolysis in soils at varying rates depending upon the 

physical characteristics of the soil such as moisture, pH, and percentage of organic matter. Environmental 

conditions such as ambient temperature and amount of sunlight also affect the persistence of guthion. 

Since sunlight is rapidly attenuated as a function of soil depth and hydrolysis is only significant in moist 

alkaline soils, biodegradation is likely to be the major transformation pathway for guthion under ordinary 

environmental conditions. A soil photolysis half-life of 180 days was reported for guthion applied to a 

sandy loam soil (pH 5.1) during the month of January in Kansas City, Missouri (EPA 1999a). In a 

subsequent study, the estimated half-life was 66 days when guthion was applied to sterile sandy loam soil 

(pH 7) and exposed to natural sunlight (California EPA 2004). After correcting for nonphotolytic 

degradation, the estimated half-life was 241 days. No degradation products were identified in either of 

these two experiments. 

The aerobic degradation of 14C labeled guthion in a sandy loam soil was studied under laboratory 

conditions over the course of a 1-year incubation period (EPA 1999a). The time for 50% dissipation 

(DT50) was 27 days and the DT90 of guthion in this soil was 146 days. Although it was observed that the 

degradation rate did not closely follow first-order kinetics, a nonlinear regression of the concentration 

versus time profile yielded an estimated half-life of 32 days (EPA 1999a). No single identified metabolite 

was found at >10% of the initially applied radioactivity; the oxygen analog of guthion peaked at 5.3% of 

the applied radioactivity 186 days after application. Four metabolites, mercaptomethyl benzazimide, 

hydroxymethyl benzazimide, benzazimide, and bismethyl benzazamide sulfide, were reported as a single 

metabolite, with a maximum of 12% of the applied amount observed at 120 days postapplication. Only 
GUTHION 121 

6. POTENTIAL FOR HUMAN EXPOSURE 

4.1% of residues were trapped as 14CO2. The majority of the radioactivity (72%) was in unidentified soilbound residues at the end of the experiment. Under anaerobic conditions, the estimated half-life of 

guthion in soil was calculated as 66 days (EPA 1999a). 

Field dissipation studies using alfalfa fields in California indicated a fairly rapid rate of dissipation. 

Guthion applied at a rate of 3 pounds a.i./A in August to a Salinas silt loam (pH 6.9–8.0) located in 

Watsonville, California had a DT50 of 9 days (EPA 1999a). A similar experiment was conducted using an 

alfalfa field in Fresno, California during the month of May. The soil type in this field was characterized 

as a Hesperia fine sandy loam (pH 7.6–8.7). The DT50 was 2 days in this soil following a single 

application at 3 pounds a.i./A (EPA 1999a). Both of these fields are somewhat more alkaline than typical 

soils, which may account for the relatively rapid rate of degradation. 

The DT50 of guthion in laboratory studies employing four different soils from Italy ranged from 4 to 

20 days (Diaz Diaz et al. 1995). The shortest dissipation times were observed in alkaline soils that were 

high in organic matter. The soil properties and the experimental results of this study are summarized in 

Table 6-3. 

When the initial guthion concentration in soil is very high (for example, in the case of an accidental spill), 

its persistence is expected to be much longer than when applied under general agricultural use conditions. 

Guthion, applied as an emulsifiable concentrate to plots of soil at initial levels of approximately 25,000– 

70,000 mg/kg (ppm), had DT50 values of up to 1 year, and measurable levels remained in the treated soil 

for up to 8 years (Staiff et al. 1975). 

6.3.2.4 Other Media 

Foliar wash off and foliar degradation are important environmental fate processes for guthion applied to 

plant surfaces. The presence of sensitizing agents in leaves and vegetation can result in enhanced 

photolysis, thus increasing the degradation rates of pesticides in sunlight (Floesser-Mueller and Schwack 

2001). Foliar degradation half-lives on plants and leaves have been reported to range from 1.6 to 

16.0 days for guthion (EPA 1999a). Louisiana sugarcane crops treated with guthion at an application rate 

of 0.82 kg/ha (3 times annually) had foliar dissipation half-lives of approximately 2–8 days (Granovsky et 

al. 1996). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Soil Properties and Degradation Rate of Guthion in Four Italian Soils 

Percent organic 

Soil type pH matter Percent clay Percent silt Percent sand DT50 (days)a 

Sandy 7.70 0.7 12.8 8.7 76.8 20 

Orchard 7.41 8.8 17.3 22.7 61.2 4 

Agricultural 7.38 3.7 18.8 23.4 60.8 5 

Volcanic 4.86 4.1 21.2 28.3 52.2 12 

a

DT50 is the time required for 50% dissipation of the initially applied amount of guthion. 

Source: Diaz Diaz et al. 1995 
GUTHION 123 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to guthion depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

guthion in unpolluted atmospheres and in pristine surface waters are often so low as to be near the limits 

of current analytical methods. In reviewing data on guthion levels monitored or estimated in the 

environment, it should also be noted that the amount of chemical identified analytically is not necessarily 

equivalent to the amount that is bioavailable and the presence/detection of guthion does not necessarily 

indicate an adverse biological effect. The analytical methods available for monitoring guthion in a variety 

of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Guthion has been infrequently detected in atmospheric samples collected throughout the United States. 

Weekly composite rainfall samples that were obtained in urban and agricultural regions of the 

Midwestern United States and along the Mississippi River indicated a low frequency of detection for 

guthion from April to September 1995 (Majewski et al. 2000). Guthion was not detected in any samples 

of rainfall from a background location (Eagle Harbor, Michigan) where it had no known use. Guthion 

was detected in approximately 10% of the rainfall samples collected in agricultural areas of Mississippi 

and in approximately 5% of the rainfall samples collected in an urban area (Jackson, Mississippi). 

Guthion was not detected in rainfall samples obtained in either agricultural or urban areas of Iowa, but 

was detected in approximately 1% of the rainfall samples collected in an agricultural location in 

Minnesota (Majewski et al. 2000). During the same collection period, guthion was identified, not 

quantified, in approximately 20% of the vapor-phase and particulate-phase air samples collected from 

Rolling Forks, Mississippi (agricultural location), but was not detected in air samples collected in 

Jackson, Mississippi (Coupe et al. 2000; Foreman et al. 2000). 

Guthion was detected in 36% of the atmospheric samples obtained near locations in Kern and Glenn 

Counties, California where it was being used as an insecticide on almond crops (Baker et al. 1996). The 

24-hour mean concentration was 0.035 μg/m3

 and the maximum concentration was 0.11 μg/m3. The 

maximum concentration observed in the air at the application site was 1.6 μg/m3

 (Baker et al. 1996). 

During application of insecticides to an apple orchard in Massachusetts approximately 1 acre in size by 

airblast ground sprayers, guthion applied at 0.75 kg/ha was detected downwind of the spray zone (75 feet 

away) at a maximum concentration of 3.87 μg/m3

 (Clark et al. 1991). Within 2 hours, the atmospheric 

level was reduced to 0.031 μg/m3

 as deposition processes transported the insecticide to the ground. 
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6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.2 Water 

Guthion has moderate to low mobility in soils and therefore has limited potential to leach into 

groundwater. Biotic and abiotic degradation that occurs in soils may also limit the leaching potential of 

guthion. Guthion was only detected (detection limit 0.001 μg/L) in 4 out of 2,451 groundwater samples 

collected from 1992 to 1996 in 20 major hydrological basins across the United States (Kolpin et al. 2000). 

The maximum observed concentration in these four positive samples was 0.18 μg/L. Guthion was not 

detected in 94 shallow groundwater wells sampled in 1992 in the Midwestern United States (Kolpin et al. 

1995). In a compilation of groundwater data from 1971 to 1991, the EPA initially reported that guthion 

was detected in 5 out of 30 wells sampled in the state of Virginia in 1987 at levels ranging from 0.04 to 

2.87 μg/L (EPA 1992b). According to an environmental fate and exposure assessment for guthion, these 

values are incorrect (EPA 1999a). According to this risk assessment there were 16 detections of guthion 

obtained from 60 wells sampled in July and August of 1987 in Clarke and Frederick County in the 

Shenandoah Valley. However, guthion was not detected in 1,598 other wells sampled in California, 

Indiana, Georgia, Hawaii, Maine, New York, Oklahoma, Rhode Island, or Texas from 1983 to 1991 (EPA 

1992b, 1999a). Guthion was not detected in 68 wells sampled in 12 counties of California from July 1, 

1994 to June 30, 1995 (California EPA 1995). 

Very little data exist for guthion in finished drinking water; however, limited monitoring data suggest that 

its occurrence is not widespread. In a cumulative risk assessment for organophosphate pesticides, the 

EPA Office of Pesticide Programs (OPP) performed a 2-year pilot reservoir monitoring study of raw and 

finished water data for 18 active organophosphate parent compounds and 13 transformation products 

(EPA 2002). Guthion was detected in 8 out of 321 raw water samples at a mean concentration of 

0.077 μg/L and a maximum concentration of 0.144 μg/L. Guthion was detected in 5 out of 225 finished 

drinking water samples at a mean concentration of 0.059 μg/L and a maximum concentration of 

0.114 μg/L. The main metabolite in chlorinated waters, gutoxon was detected in 1 out of 316 raw water 

samples at a concentration of 0.263 μg/L and in 4 out of 219 finished drinking water samples at a mean 

concentration of 0.18 μg/L and a maximum concentration of 0.26 μg/L (EPA 2002). Guthion or the oxon 

metabolite was only detected in drinking water samples collected from Missouri, New York, Oklahoma, 

and South Carolina. Guthion and its metabolite were not detected in raw or treated water samples 

obtained from California, Indiana, Louisiana, North Carolina, Ohio, Pennsylvania, South Dakota, or 

Texas (EPA 2002). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Due to spray drift, runoff, and erosion of treated soils, guthion is frequently detected in surface waters 

adjacent to farming areas where it has been applied as an insecticide. The U.S. Geological Survey 

maintains and operates The National Water Quality Assessment Program (NAWQA) database, which 

frequently updates groundwater and surface water monitoring data for various pesticides, including 

guthion, in >50 major river basins in the United States. Data from 1991, 1994, and 1997 indicated that 

guthion was detected in 1.31% of 1,800 water samples collected at 75 streams near agricultural locations 

in the United States. The maximum concentration of guthion in these streams was reported as 0.5 μg/L 

(USGS 2003). 

Guthion was detected in 13 out of 142 surface water samples collected at four sites in the San Joaquin 

River Basin at a maximum concentration of 0.39 μg/L (Dubrovsky et al. 2000). Guthion levels at these 

sites tended to spike during the summer months, coinciding with the agricultural season and then decrease 

during the winter. For example, guthion levels in Orestimba Creek in the San Joaquin River Basin 

fluctuated between 0.1 and 0.2 μg/L from June to September 1992, and then decreased sharply from 

November 1992 to May 1993, before increasing to 0.4 μg/L in June 1993 (USGS 1999). Guthion was 

detected in 64 out of 98 surface water samples at a maximum concentration of 0.523 μg/L obtained from 

various sites in a heavy apple growing region along the Yakima River Basin, Washington during the 

period of May 1999 through January 2000 (USGS 2001). The study authors noted that concentrations of 

guthion exceeded its chronic-toxicity guideline for the protection of aquatic life in 50% of the samples. 

Monitoring data from the Washington State Department of Agriculture from April to October 2004, 

reported guthion levels of 0.013–0.042 μg/L (4 positive detections out of 31 samples) in the Sulphur 

Creek Wasteway near its confluence with the Yakima River (Burke et al. 2005). In addition, it was 

detected in 4 out of 45 samples obtained from Spring Creek near its confluence with the Yakima River at 

levels ranging from 0.014 to 0.023 μg/L (Burke et al. 2005). Sampling data from April to December 

2003 in Sulphur Creek had 11 positive detections of guthion with a maximum concentration of 

0.025 μg/L (Anderson et al. 2004). Guthion was detected in 0.5% of the surface water samples collected 

in two streams located in Oregon, at a maximum concentration of 0.171 μg/L (Hoffman et al. 2000). 

Guthion was detected in 12 out of 29 surface water samples obtained from a creek (Crab Creek Lateral) 

that feeds into Royal Lake, in Central Washington State during March 1993 to May 1994 sampling 

(Gruber and Munn 1998). The maximum observed concentration was 0.2 μg/L. It was reported that most 

of the flow of water into Crab Creek Lateral is the result of excess irrigation water that enters the canal 

from agricultural drains and groundwater discharges. An analysis of pesticide residues in U.S. 

groundwater and streams from 1992 to 2001 was recently summarized by analyzing data in the NAWQA 

database (USGS 2006a). Guthion exceeded benchmark levels (0.18 μg/L for acute fish toxicity, 
GUTHION 126 

6. POTENTIAL FOR HUMAN EXPOSURE 

0.36 μg/L for chronic fish toxicity, 0.08 μg/L for acute invertebrate toxicity, 0.16 μg/L for chronic 

invertebrate toxicity) for aquatic life in approximately 20% of the agricultural streams and 10% of the 

urban streams included in the sampling program (USGS 2006a). Guthion was detected in 11 water 

samples at a maximum concentration of 0.034 μg/L collected from four major irrigation return-flow 

drainage basins, in agricultural areas of Washington State from July 2002 through October 2004 (USGS 

2006b). 

The EPA Office of Water maintains the STOrage and RETrieval (STORET) database, which contains 

data for guthion in surface water throughout the United States. Information from this database is of 

limited value because it is difficult to determine the purpose and circumstances of the studies contained in 

the database. According to the studies included in STORET, only 15 out of 1,123 samples at 653 sites 

had detectable levels of guthion in the United States over a multi-year period (EPA 1999a). These data 

are summarized in Table 6-4. Data maintained in the STORET database for 2005–2006 did not include 

any positive detections of guthion in water samples (EPA 2006k). 

6.4.3 Sediment and Soil 

Guthion was detected at levels of <0.1 mg/kg in surface soils (upper 6 inches) of Marengo, Alabama 

(Albright et al. 1974). Soil samples collected from 48 homes of agricultural families in eastern 

Washington State had mean guthion levels of 60 μg/kg (range: not detected to 814 μg/kg), while soil 

samples collected from 11 homes of nonagricultural families had no detectable levels of guthion 

(detection limit 32 μg/kg) (Simcox et al. 1995). For the homes of the agricultural families, a positive 

correlation was observed between guthion levels in the soil and household dust, and the proximity to 

nearby apple orchards (Simcox et al. 1995). In a study of 49 randomly chosen agrichemical facilities 

located throughout the state of Illinois, guthion was detected in soil samples at 5 of the 10 sites that 

processed, used, or handled it (Krapac et al. 1995). The mean, median, and range of guthion 

concentrations in the soil samples at these five sites were reported as 148, 110, and 45–878 μg/kg, 

respectively. 

Data maintained in the STORET database for 2005–2006 included seven detections of guthion in 

sediment samples obtained from Escambia County, Florida at concentrations ranging from 6.6 to 

23 μg/kg (EPA 2006k). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Guthion Levels in Surface Water from the STORET Database 

Number of Number of Number of Maximum 

Water body samples detects sites concentration (μg/L) Years 

Canals 289 3 63 0.01 1974–1993 

Estuaries 185 2 162 3 1969–1997 

Lakes 406 1 242 0.01 1974–1996 

Oceans 16 0 6 Not applicable 1980–1985 

Reservoirs 91 9 57 0.01 1975–1995 

Springs 136 0 123 Not applicable 1987–1996 

Source: EPA 1999a 
GUTHION 128 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.4 Other Environmental Media 

Guthion has frequently been detected in foods in the United States, primarily in fruits and vegetables. In 

2002, the EPA Office of Pesticides Programs published a cumulative risk assessment that evaluated the 

cumulative dietary risk due to the use of organophosphate pesticides on food crops (EPA 2002). In this 

assessment, residue monitoring data collected by the U.S. Department of Agriculture’s Pesticide Data 

Program (USDA-PDP) supplemented with information from the FDA Center for Food Safety and 

Applied Nutrition (FDA/CFSAN) were analyzed. Residue data were collected on approximately 44 food 

commodities monitored by PDP between the years 1994 and 2000. The data pertaining to guthion are 

summarized in Table 6-5. In general, guthion was detected at levels below 1 ppm in most food items, 

although a single maximum occurrence of 1.9 ppm was reported for guthion in pears (EPA 2002). Data 

from the FDA Total Diet Study Market Basket Survey from 1991 to 2001 indicated that guthion was 

detected in 15 out of 320 food items in the surveys. It was most frequently detected in red apples 

(32 detections with a maximum concentration of 0.19 ppm) and pears (29 detections with a maximum 

concentration of 0.227 ppm), but was also detected in nonfruit or vegetable items including cheddar 

cheese and blueberry muffins (FDA 2003). 

Over a 5-year period (1991–1995), guthion was detected in 295 out of 2,338 fruits and vegetables 

analyzed in a market basket survey in Canada (Ripley et al. 2000). Only two other pesticides 

(dithiocarbamate and captan) were detected more frequently in fruits and vegetables than guthion in this 

Canadian survey. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The general population is primarily exposed to guthion through the ingestion of food items, although 

minor exposure may occur from inhalation of ambient air and ingestion of drinking water. Urinary 

metabolites that are reflective of exposure to guthion were measured as a part of the National Health and 

Nutrition Examination Surveys (NHANES) (CDC 2005). These dialkyl phosphate metabolites are not 

specific to guthion, but their detection indicates the possibility of exposure to guthion and several other 

organophosphate pesticides. Dialkyl phosphates may also be present in the environment from the 

degradation of these pesticides. Therefore, in addition to reflecting exposure to guthion or other 

organophosphate pesticides, the presence of the metabolites in a person’s urine may also reflect exposure 

to the metabolite itself (CDC 2005). Six dialkyl phosphates were measured in the most recent NHANES 

and the results for the three compounds that are known metabolites of guthion, dimethyl phosphate 

(DMP), dimethyl thiophosphate (DMTP), and dimethyl dithiophosphate (DMDTP) are reported in 
GUTHION 129 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Guthion Residues in Various Foods from 1994 to 2000 

Number Number of Average Maximum 

Food item analyzed detections concentration (ppm)a concentration (ppm) 

Apple juice 1,554 81 4.9x10-5 0.008 

Apples 2,471 1,228 0.028 0.46 

Apples (single serving) 377 220 0.022 0.77 

Bananas 1,126 0 0 0 

Broccoli 678 0 0 0 

Cantaloupe 1,640 0 0 0 

Carrots 2,072 0 0 0 

Celery 176 0 0 0 

Cherries 275 163 0.027 0.44 

Corn Syrup 423 0 0 0 

Cucumbers 1,467 0 0 0 

Grape juice 1,379 0 0 0 

Grapes 2,625 41 0.00119 0.47 

Green beans (canned) 853 0 0 0 

Green beans (fresh) 1,897 9 1.2x10-4 0.051 

Green beans (frozen) 729 3 1.2x10-4 0.038 

Lettuce 1,616 0 0 0 

Milk 1,892 0 0 0 

Nectarines 345 48 0.0049 0.2 

Oats (bran) 45 0 0 0 

Oats (rolled) 287 0 0 0 

Orange juice 1,392 0 0 0 

Oranges 2,636 2 3.5x10-5 0.073 

Peaches (canned) 754 1 7.0x10-5 0.053 

Peaches (fresh) 1,623 511 0.022 0.72 

Peaches (single serving) 534 218 0.0214 0.65 

Pears (canned) 737 0 0 0 

Pears (fresh) 1,773 1,039 0.0503 1.9 

Pears (single serving) 696 275 0.0318 0.87 

Pineapples 104 0 0 0 

Potatoes 1,770 0 0 0 

Poultry (adipose tissue) 476 0 0 0 

Poultry (liver) 479 0 0 0 

Poultry (muscle) 145 0 0 0 

Soybean grain 748 0 0 0 

Spinach (canned) 863 0 0 0 

Spinach (fresh) 1,639 4 4.46x10-4 0.4 

Spinach (frozen) 714 1 1.8x10-5 0.013 

Strawberries (fresh) 1,768 2 1.52x10-4 0.2 

Strawberries (frozen) 155 3 0.001781 0.2 
GUTHION 130 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Guthion Residues in Various Foods from 1994 to 2000 

Number Number of Average Maximum 

Food item analyzed detections concentration (ppm)a concentration (ppm) 

Straw bell peppers 1,468 9 1.9x10-4 0.11 

Sweet corn (canned) 652 0 0 0 

Sweet corn (fresh) 19 0 0 0 

Sweet corn (frozen) 635 0 0 0 

Sweet peas (canned) 746 0 0 0 

Sweet peas (fresh) 9 0 0 0 

Sweet peas (frozen) 703 0 0 0 

Sweet potatoes 1,559 0 0 0 

Tomatoes (canned) 737 5 8.4x10-5 0.013 

Tomatoes (fresh) 1,960 31 0.000748 0.71 

Wheat 940 3 7.0x10-5 0.022 

Winter squash (fresh) 1,216 0 0 0 

Winter squash (frozen) 470 0 0 0 

a

Nondetects were counted as zero in calculating the average. 

Source: EPA 2002 
GUTHION 131 

6. POTENTIAL FOR HUMAN EXPOSURE 

Tables 6-6, 6-7, and 6-8. A general reduction in urinary levels of these metabolites has been observed 

from the 1999–2000 survey data with the levels from the 2001–2002 data. 

The average daily dietary intake (AVDI) of guthion categorized by age and gender groups is shown in 

Table 6-9. These data were developed from the FDA Total Diet Study (TDS), which collects foods from 

several regional and metropolitan areas that are representative of the total diet of the U.S. population. 

These dietary intake values are lower than several toxicological benchmark values including the World 

Health Organization (WHO) Acceptable Daily Intake (ADI) of 5 μg/kg/day and the EPA Office of 

Pesticides Program’s acute oral reference value of 3 μg/kg/day (EPA 1999b, 2001b; Fenske et al. 2000a). 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Similar to adults, children are primarily exposed to guthion through the ingestion of foods. The dietary 

AVDI of guthion has been reported as 0.069–0.083 μg/kg-body weight/day for 6–11-month-old infants 

and 0.022–0.031 μg/kg-body weight/day for 2-year-old toddlers (Gunderson 1988, 1995). No 

measurements have been made of guthion in amniotic fluid, meconium, cord blood, neonatal blood, or 

any other tissues that may indicate prenatal exposure. No data have been reported on the levels of 

guthion in breast milk. The metabolite DMP was detected in 1 out of 20 postpartum meconium samples 

obtained from newborn infants at the New York Presbyterian Hospital (Whyatt and Barr 2001). The 

metabolites DMTP and DMDTP were not detected. A study conducted in Rio Negro, Argentina analyzed 

the acetylcholinesterase activity in placenta tissue and plasma of 200 pregnant females (Souza et al. 

2005). Guthion is a frequently used pesticide in this heavy apple and pear growing region. A correlation 
GUTHION 132 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Selected Percentile Urine Concentrations (μg/L) of DMP in the U.S. 

Population from 1999 to 2002a

Percentile 

Group 50th 75th 90th 95th Sample size 

Age 6 and older 

 1999–2000 0.740 2.80 7.90 13.0 1,949 

 2001–2002 <LOD 3.25 8.22 13.4 2,519 

6–11 Years 

 1999–2000 1.00 4.40 10.0 21.0 471 

 2001–2002 0.970 5.03 12.2 18.2 576 

12–19 Years 

 1999–2000 0.650 3.80 9.90 22.0 664 

 2001–2002 0.670 4.27 9.27 14.6 822 

20–59 Years 

 1999–2000 0.680 2.60 6.50 9.70 814 

 2001–2002 <LOD 2.93 6.89 11.5 1,121 

Males 

 1999–2000 0.650 2.80 7.90 18.0 952 

 2001–2002 <LOD 3.40 8.22 12.6 1,187 

Females 

 1999–2000 0.780 2.80 7.60 10.0 997 

 2001–2002 <LOD 3.05 8.34 13.7 1,332 

Mexican Americans

 1999–2000 1.00 3.80 9.50 15.0 672 

 2001–2002 0.660 3.22 9.38 14.4 678 

Non-Hispanic blacks 

 1999–2000 0.980 3.60 8.90 21.0 509 

 2001–2002 0.910 5.45 11.5 19.4 695 

Non-Hispanic whites 

 1999–2000 <LOD 2.90 7.90 10.0 595 

 2001–2002 <LOD 3.01 7.39 12.3 948 

a

The proportion of the results below the LOD was too high to calculate geomethric means for DMP. 

DMP = dimethyl phosphate; LOD = limit of detection 

Source: CDC 2005 
GUTHION 133 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-7. Geometric Mean and Selected Percentile Urine Concentrations (μg/L) 

of DMTP in the U.S. Population from 1999 to 2002 

Geometric Percentile 

Group mean 50th 75th 90th 95th Sample size 

Age 6 and older 

 1999–2000 1.82 2.70 10.0 38.0 46.0 1,948 

 2001–2002 a 0.450 4.02 16.2 32.6 2,518 

6–11 Years 

 1999–2000 2.72 4.10 20.0 40.0 62.0 471 

 2001–2002 a 1.44 8.33 28.2 45.7 575 

12–19 Years 

 1999–2000 2.53 3.60 16.0 37.0 69.0 664 

 2001–2002 a 1.03 4.83 20.8 33.9 822 

20–59 Years 

 1999–2000 1.59 2.20 9.10 38.0 38.0 813 

 2001–2002 a <LOD 3.32 13.6 29.5 1,121 

Males 

 1999–2000 2.10 3.40 13.0 38.0 41.0 952 

 2001–2002 a 0.610 4.21 18.3 30.4 1,187 

Females 

 1999–2000 1.59 2.00 9.70 38.0 52.0 996 

 2001–2002 a <LOD 3.76 15.9 34.3 1,331 

Mexican Americans

 1999–2000 1.79 2.00 10.0 38.0 130 671 

 2001–2002 a <LOD 3.74 15.1 35.2 678 

Non-Hispanic blacks 

 1999–2000 2.13 3.60 11.0 37.0 39.0 509 

 2001–2002 a 1.25 5.54 20.6 42.2 695 

Non-Hispanic whites 

 1999–2000 1.77 2.60 11.0 38.0 45.0 595 

 2001–2002 a <LOD 3.99 17.0 32.6 947 

a

The proportion of the results below the LOD was too high to calculate a geometric mean. 

DMTP = dimethyl thiophosphate; LOD = limit of detection 

Source: CDC 2005 
GUTHION 134 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-8. Selected Percentile Urine Concentrations (μg/L) of DMDTP in the U.S. 

Population from 1999 to 2002a

Percentile 

Group 50th 75th 90th 95th Sample size 

Age 6 and older 

 1999–2000 <LOD 2.30 12.0 19.0 1,949 

 2001–2002 <LOD 0.890 0.49 4.95 2,518 

6–11 Years 

 1999–2000 0.730 4.30 16.0 32.0 471 

 2001–2002 <LOD 1.30 3.53 7.33 575 

12–19 Years 

 1999–2000 <LOD 2.20 12.0 19.0 664 

 2001–2002 <LOD 0.810 2.51 4.63 821 

20–59 Years 

 1999–2000 <LOD 2.10 10.0 16.0 814 

 2001–2002 <LOD 0.840 2.32 4.90 1,122 

Males 

 1999–2000 0.110 2.30 16.0 18.0 952 

 2001–2002 <LOD 0.840 2.40 5.13 1,187 

Females 

 1999–2000 <LOD 2.10 10.0 20.0 997 

 2001–2002 <LOD 0.950 2.52 5.10 1,331 

Mexican Americans

 1999–2000 0.240 1.80 5.70 12.0 672 

 2001–2002 <LOD 0.960 2.66 4.47 678 

Non-Hispanic blacks 

 1999–2000 0.330 3.20 14.0 18.0 509 

 2001–2002 <LOD 0.750 2.11 4.38 695 

Non-Hispanic whites 

 1999–2000 <LOD 2.00 13.0 20.0 595 

 2001–2002 <LOD 0.940 2.49 5.74 947 

a

The proportion of the results below the LOD was too high to calculate geomethric means for DMDTP. 

DMDTP = dimethyl dithiophosphate; LOD = limit of detection 

Source: CDC 2005 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-9. Dietary Average Daily Intake of Guthion (μg/kg/day) 

1982–1984a 1986–1991b 

6–11 Months 0.0069 0.0083 

2 Years 0.022 0.0311 

14–16 Years (female) 0.0048 0.0061 

14–16 Years (male) 0.0050 0.0073 

25–30 Years (female) 0.0046 0.0061 

25B30 Years (male) 0.0033 0.0044 

60B65 Years (female) 0.0062 0.0079 

60B65 Years (male) 0.0051 0.0064 

a

Gunderson 1988 b

Gunderson 1995 
GUTHION 136 

6. POTENTIAL FOR HUMAN EXPOSURE 

between acetylcholinesterase activity in plasma and timing of pesticide applications was observed. An 

18% reduction in maternal plasma acetylcholinesterase activity was observed during the pesticide 

application months of November–February as compared to samples collected in non-application months 

(March–October); however, a slight increase in activity was observed in placenta tissue during the 

pesticide application months. 

Nondietary ingestion may be an important exposure pathway in agricultural areas, where guthion is used 

as an insecticide. The tendency of young children to ingest soil, either intentionally through pica or 

unintentionally through hand-to-mouth activity, is well documented. These behavioral traits can result in 

ingestion of guthion present in soil and dust. Young children often play on the ground or on carpets and 

this will increase the likelihood of dermal exposure and inhalation of contaminated particles from soil, 

household dust, and treated surfaces. The exposure of young children to organophosphate pesticides, 

including guthion, in an agricultural community in central Washington was studied by collecting spot 

urine and hand wipe samples from a group of 109 children aged 6 months to 6 years during the pesticide 

spraying months of May–July (Lu et al. 2000). Participants included 62 agricultural families 

(49 applicators and 13 farm workers) and 14 reference families in which no family member was 

employed in occupations requiring contact with pesticides, and the residence was located at least one 

quarter mile away from any pesticide treated orchard. There were 72, 19, and 18 children of pesticide 

applicators, farm workers, and reference families, respectively. The median urinary levels of the dimethyl 

metabolites DMTP and DMDTP were 0.05 μg/mL in the children of the agricultural families and 

0.01 μg/mL in the children of reference families (Lu et al. 2000). Approximately 67% of the urine 

samples collected from the children of farm applicator and farm workers contained detectable levels of 

DMTP, while 53% of the urine samples collected from the children of reference families contained 

detectable levels. Wipes obtained from the hands of the children indicated that detectable levels of 

guthion were present in approximately 13% of the children’s hands from agricultural families; while none 

of the children from the reference families had detectable levels of guthion in hand wipe samples. 

Additional exposure to guthion may also arise from the clothing or personal items of adults that are 

employed in pesticide application or other farm work. For instance, the mean guthion level on the surface 

of work boots in the agricultural families was 0.03 μg/cm2

 and the mean level on the steering wheel of the 

family vehicle was 0.001 μg/cm2

 (Lu et al. 2000). Guthion was not detected on personal clothing items or 

in the vehicles of the 14 reference families. 

Urinary levels of dialkyl phosphates were monitored in children residing in agricultural communities in 

Washington State over a 21-month period (Koch et al. 2002). Although several pesticides are used in this 
GUTHION 137 

6. POTENTIAL FOR HUMAN EXPOSURE 

area, the authors reported that guthion is the most frequently applied insecticide in the agricultural region 

studied. The overall geometric mean urinary level of combined DMP, DMTP, and DMDTP was reported 

as 0.080 μmols/L for all samples collected over this 21-month period. The highest levels of dialkyl 

phosphates measured in the urine coincided with the orchard spraying season (geometric mean of 

0.096 μmols/L), while the lowest levels were observed during the winter nonspraying months (geometric 

mean of 0.072 μmols/L). A similar study was conducted by measuring the combined levels of DMP, 

DMTP, and DMDTP in the urine of children from 218 farm workers households in agricultural 

communities of Washington State (Curl et al. 2002). DMP, DMTP, and DMDTP were identified in 19, 

88, and 45%, respectively, of the 211 urine samples collected and the geometric mean concentration of 

the combined dialkyl phosphate metabolites was 0.09 μmols/L (Curl et al. 2002). Urine samples collected 

from 88 children in central Washington State indicated that DMTP was quantified more often in the urine 

of children of pesticide applicators when compared with reference children (Loewenherz et al. 1997). 

Detectable levels of DMTP were observed in 47% of the urine samples obtained from the children of 

pesticide applicators, compared to 27% for the reference group. The median DMTP concentration in the 

urine of the agricultural children was 0.021 μg/mL (0.15 μmols/L) compared to 0.005 μg/mL 

(0.035 μmols/L) for the reference children (Loewenherz et al. 1997). 

Aggregate dose estimates for guthion and phosmet were calculated for children in an agricultural 

community in the state of Washington (Fenske et al. 2000a). These estimates were generated from the 

urinary metabolite concentrations of DMTP and DMDTP in 109 children up to 6 years of age residing in 

this community. Since guthion and phosmet were the organophosphates most often used in this area, it 

was assumed that the dialkyl phosphate metabolites measured in urine samples were due exclusively to 

these two pesticides. The mean (± standard deviation) creatinine adjusted dose for the children of 

agricultural families was 3.5 (±4.2) μg/kg/day during the 6–8-week spraying season (May—July), as 

compared to 2.0 (±3.1) μg/kg/day for reference children. The mean creatinine adjusted single day dose 

was 3.7 (±5.9) μg/kg/day for children of agricultural families as compared to 2.1±4.1 μg/kg/day for 

reference children (Fenske et al. 2000a). Although the large standard deviation suggests a high degree of 

variability, these estimated intakes are much larger than the FDA estimated dietary intakes of the general 

population (Gunderson 1988, 1995) and are of the same order of magnitude as the WHO ADI of 

5 μg/kg/day. 

These findings suggest that children in agricultural communities where guthion is used as an insecticide 

are potentially exposed more frequently and to higher levels than children in the general population 

through nondietary exposure pathways. 
GUTHION 138 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Pesticide applicators, farm workers, and people living in close proximity to agricultural areas such as 

apple and cherry orchards where guthion is frequently used are potentially exposed to higher levels of 

guthion than the general population. In addition to ingestion of contaminated foods, inhalation and 

dermal exposures to farm workers and their families are considerably higher than for the general 

population. Household dust and soil samples were collected from 59 residences in Washington State 

(Simcox et al. 1995). The households were classified as 26 farming, 22 farm workers, and 11 nonfarming 

families. The majority of agricultural families inhabited homes within 200 feet of an operating apple or 

pear orchard. The mean concentration of guthion in household dust of the 48 agricultural households was 

1.870 μg/g (0.170–11.270 μg/g range), while the mean concentration in household dust of the 

nonagricultural homes was 0.330 μg/g (0.134–0.816 μg/g range) (Simcox et al. 1995). Household dust 

samples were collected from the homes of 96 farm workers and 24 apple growers in Oregon to assess 

potential exposure of migrant farm workers to organophosphate pesticides in this community (McCauley 

et al. 2001). Mean levels of guthion in dust samples were 1.45 μg/g in the homes of farm workers and 

1.64 μg/g in the homes of growers. The mean guthion level in household dust samples collected from the 

homes of 62 agricultural families in central Washington State was 1.94 μg/g (Lu et al. 2000). The mean 

guthion level in household dust obtained from the homes of 14 reference families was 0.29 μg/g. This 

represents an approximate 7-fold greater guthion exposure level in the homes of agricultural workers as 

compared to nonagricultural families. Levels of guthion in household dust samples were also shown to be 

highest among residences closest to the pesticide-treated apple orchards (Lu et al. 2000). Guthion was 

detected in 133 out of 156 household dust samples and 165 out of 190 vehicle dust samples from 

agricultural workers in Washington State (Curl et al. 2002). The geometric mean concentration in house 

dust was reported as 0.53 μg/g (14.9 μg/g maximum level), while the geometric mean concentration of 

guthion in vehicle dust was reported as 0.75 μg/g (38.3 μg/g maximum level). 

The urinary levels of DMP, DMTP, and DMDTP were measured in 11 workers engaged in thinning and 

picking practices in a peach orchard that had been sprayed 20 days prior with chlorpyrifos methyl and 

guthion (Aprea et al. 1994). The average level of the three metabolites in the urine of workers wearing 

different types of protective equipment in the peach orchard during work operations ranged from 

approximately 470 to 940 nmols/g creatinine, depending on the type of equipment used. A separate 

subject not wearing gloves or a mask during work operations had a mean urinary level of nearly 

4,000 nmols/g creatinine for the three metabolites (Aprea et al. 1994). A control group of 
GUTHION 139 

6. POTENTIAL FOR HUMAN EXPOSURE 

99 nonoccupationally exposed persons had a mean urinary level of approximately 200 nmols/g creatine. 

The authors concluded that the main route of guthion absorption to the workers was from dermal 

exposure, but that respiratory exposure was also significant (Aprea et al. 1994). 

Dermal absorption of guthion in humans and animals have been demonstrated in several studies. The 

amount of guthion absorbed through human skin was studied by applying 500–6,000 μg guthion to the 

forehead of volunteers and monitoring the level of DMTP excreted in urine over a 72-hour period 

(Franklin et al. 1986). The results of this pilot study are summarized in Table 6-10. The authors 

concluded that approximately 30–40% of the applied dose was absorbed in humans, as compared to 

nearly 100% in rats and rabbits (Franklin et al. 1986). This estimate is somewhat higher than other 

estimates from experimental data. As summarized in a risk characterization document developed by the 

California EPA, guthion was applied topically to the forearms of six volunteers in isopropyl alcohol at 

2.6 and 9.2 μg/cm2

 or in an aqueous suspension of Guthion 25 WP at 4.7 μg/cm2 for an exposure period 

of 8 hours (California EPA 2004). Blood samples were collected up to 5 days postapplication and urine 

and feces were collected for 13 days postapplication. The dermal absorption was measured as the sum of 

the radioactivity in the urine, feces, and tape stripping. The dermal absorption ranged from 21.5% for 

aqueous suspension of the wettable powder to 27.8% for the technical-grade material applied in isopropyl 

alcohol at the lower concentration. Another study summarized in this document estimated the dermal 

absorption of guthion in an acetone-based solution as 16% (California EPA 2004). Absorption of guthion 

applied to the skin of male rats continued following application with subsequent washing with water, and 

the amount of absorption was observed to be dose-dependent (Zendzian 2003). 

In conclusion, agricultural workers and their families are likely to be exposed more frequently, and to 

higher levels of guthion than the general population if they are involved with procedures such as spraying, 

harvesting, or thinning of crops in which guthion has been applied as an insecticide. In addition to 

ingesting food items containing guthion, agricultural workers and their families may be subject to 

additional dermal and inhalation exposures from dusts, soils, and personal items such as clothing 

contaminated with guthion. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of guthion is available. Where adequate information is not 
GUTHION 140 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Excretion of DMTP Following the Dermal Application of Guthion to 

Volunteers 

Cumulative DMTP total in urine (μg) 

Dose (μg/person) 24 hours 48 hours 72 hours DMTP/guthiona 

500 54 76 85 17 

1,000 96 130 152 15 

2,000 56 90 119 6 

4,000 154 267 404 10 

6,000 153 284 323 5 

a

Cumulative amount of DMTP excreted divided by amount of guthion applied, multiplied by 100. 

DMTP = dimethyl thiophosphate 

Source: Franklin et al. 1986 
GUTHION 141 

6. POTENTIAL FOR HUMAN EXPOSURE 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of guthion. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of guthion are 

sufficiently well defined to allow assessments of the environmental fate of this compound to be made 

(Gawlik et al. 1998; Hansch et al. 1995; Suntio et al. 1988; Tomlin 2003). Some physical and chemical 

properties of guthion that are not relevant to environmental fate are lacking. Knowledge of these 

properties, such as flashpoint and flammability limits, would be useful for workers involved in the 

manufacture, use, or clean-up of guthion; however, no data need is identified at this time. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2005, became available in May of 2007. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

There are no data available regarding the production, import, or export volumes of guthion. Many of 

guthion’s uses were cancelled by the EPA in 2001 and all remaining uses are scheduled to be cancelled by 

2012. Incineration and alkaline hydrolysis are the two methods employed to dispose of guthion. No data 

need is identified at this time. 

Environmental Fate. Sufficient data are available to characterize the environmental fate of guthion. 

When applied as an insecticide, guthion adsorbs strongly to soil surfaces and is degraded in the 

environment by a combination of biotic and abiotic reactions. It may enter nearby water bodies through 

spray drift, runoff, and erosion of treated soils where it is expected to partition to suspended solids and 
GUTHION 142 

6. POTENTIAL FOR HUMAN EXPOSURE 

sediment. Data are available regarding the rate of hydrolysis (EPA 1999a; Lartiges and Garrigues 1995), 

photolysis (EPA 1999a; Lartiges and Garrigues 1995), biodegradation (Diaz Diaz et al. 1995; EPA 

1999a), foliar dissipation (Granovsky et al. 1996), and terrestrial field dissipation for guthion (EPA 

1999a). The important transport and partitioning properties of guthion have also been studied including 

adsorption/desorption in soil (EPA 1999a; Gawlik et al. 1998) and runoff potential following its 

application (EPA 1999a). No data needs are identified at this time. 

Bioavailability from Environmental Media. Guthion is absorbed following both oral and dermal 

exposures (Fakhr et al. 1996; Franklin et al. 1986). No experimental studies were located regarding the 

bioavailability of guthion from contaminated soil, water, and air; therefore, data are needed regarding the 

bioavailability of guthion from soil and other environmental media. 

Food Chain Bioaccumulation. Data are needed regarding the food chain bioaccumulation of 

guthion. An estimated BCF value of 26 was calculated for guthion; however, experimentally determined 

BCF values in fathead minnows were significantly larger than this estimated value (Knuth et al. 2000). A 

lipid-corrected BCF value of approximately 3,000 was observed in minnows. When these lipid corrected 

BCF values were adjusted to whole-body BCF values, the data were more consistent with the estimated 

value. More experimental bioconcentration data on different species of fish along with depuration 

kinetics are required to assess this end point. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of guthion in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

guthion in the environment can be used in combination with the known body burden of guthion to assess 

the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. 

Monitoring data for guthion are available in air (Coupe et al. 2000; Foreman et al. 2000; Majewski et al. 

2000), water (California EPA 1995; EPA 1992b, 1999a, 2002; Gruber and Munn 1998; Kolpin et al. 

2000; USGS 2006a, 2006b), soil (Krapac et al. 1995; Simcox et al. 1995), and food (EPA 2002; FDA 

2003; Ripley et al. 2000). Additional data are required regarding the levels of guthion in fish and animal 

tissues. Continued monitoring of guthion residues in foods and other environmental media, particularly 

in agricultural fields where it is extensively used or from hazardous waste sites, would be helpful for 

further assessing the potential for human exposure. 
GUTHION 143 

6. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Levels in Humans. Direct monitoring data of guthion in humans is rare since its 

biological half-life is short. Metabolites such as DMP, DMTP, and DMDTP have been monitored in 

urine of individuals (Aprea et al. 1994; CDC 2005; Fenske et al. 2000a; Loewenherz et al. 1997; Lu et al. 

2000). These metabolites are not specific to guthion, but indicate potential exposure to several 

organophosphate pesticides. Continued monitoring data, particularly chronic low-level exposure data for 

humans in the vicinity of agricultural locations where it is frequently used or hazardous waste sites, are 

necessary. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Similar to adults, exposure measurements for the guthion metabolites in 

children are available (CDC 2005; Fenske et al. 2000a; Koch et al. 2002; Loewenherz et al. 1997; Lu et 

al. 2000). Children in the general population are exposed to guthion primarily through the dietary 

ingestion of contaminated food items. A unique exposure pathway exists for children of agricultural 

families that reside near farms or orchards where guthion is used. Potential exposure to guthion from 

parents clothing, family automobiles, and personal items exists (Lu et al. 2000). Since guthion has also 

been detected in soil and dust samples in or around homes where it is used, common play activities on the 

ground or pica may result in exposure for these children. Continued monitoring data is necessary for 

assessing the need to conduct health studies on exposed children. In addition, a data need exists for the 

levels of guthion or metabolites in breast milk. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for guthion were located. This substance is not 

currently one of the compounds for which a sub-registry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates 

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to 

this substance. 
GUTHION 144 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2006) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. 

Researchers at the University of California, Department of Entomology (R.I. Krieger, principal 

investigator) are studying the dermal transfer of guthion and other pesticides from treated turf and other 

environmental surfaces to children. Researchers at the Washington State University Food and 

Environmental Quality Laboratory are measuring the atmospheric deposition and spray drift 

characteristics of guthion applied to apple orchards in Washington State. 
GUTHION 145 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring guthion, its metabolites, and other biomarkers of exposure and effect to 

guthion. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to 

identify well-established methods that are used as the standard methods of analysis. Many of the 

analytical methods used for environmental samples are the methods approved by federal agencies and 

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other 

methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

The biological half-life of guthion ranges from approximately 24 to 36 hours in humans (California EPA 

2004; Loewenherz et al. 1997). As a consequence, monitoring human tissue for the parent compound 

only provides information regarding recent exposure or acute intoxication. Exposure to guthion is often 

measured by monitoring for dialkyl phosphate metabolites such as dimethyl phosphate (DMP), dimethyl 

thiophosphate (DMTP), and dimethyl dithiophosphate (DMDTP) in the urine (Koch et al. 2002) or 

measuring cholinesterase activity in plasma, red blood cells, and whole blood (Vasilic et al. 1987). These 

methods are not specific to guthion because these metabolites are produced from the breakdown of other 

organophosphate compounds as well. Therefore, monitoring for DMP, DMTP, and DMDTP provide 

information regarding the potential exposure to organophosphate pesticides in general. 

Quantification of the metabolites DMP, DMTP, and DMDTP in urine samples is typically accomplished 

using gas chromatography (GC) with nitrogen phosphate detection (NPD) or with flame photometric 

detection (FPD). Sample preparation usually includes solid-phase extraction, azeotropic distillation, and 

derivatization with pentafluorobenzylbromide (PFBB) in order to convert the dialkyl phosphate acids to 

esters (Loewenherz et al. 1997). Recoveries are usually around 90% and detection limits for the 

metabolites are in the parts per billion (ppb) range (Koch et al. 2002; Loewenherz et al. 1997). 

GC with NPD or electron capture detection (ECD) has been used to quantify levels of guthion and other 

pesticides in human serum and urine (Pitarch et al. 2001). Mass spectroscopy (MS) in ion selective mode 

is used to confirm peak identity of the suspected compounds. These analyses require either solid-phase 
GUTHION 146 

7. ANALYTICAL METHODS 

extraction (SPE) with a C18 cartridge or liquid-liquid microextraction (LLME) procedure prior to 

quantification. In general, recoveries in both urine and serum were high for guthion (≥96% depending 

upon the extraction procedure) and the detection limits are 1.7–6.0 μg/L for urine and 10 μg/L for serum 

(Pitarch et al. 2001). For human serum samples, the authors determined that the SPE extraction 

procedure was the preferred method since it was faster, less tedious, and avoided the formation of 

emulsions that were frequently encountered in the LLME procedure. 

Organophosphates such as guthion cause toxic effects in humans primarily through the inhibition of 

acetylcholinesterase enzyme. Spectroscopic methods of measuring the depression of cholinesterase 

activity are based on the Ellman method (Ellman et al. 1961). Acetylthiocholine is hydrolyzed by 

acetylcholinesterase (AChE—also referred to as erythrocyte acetylcholinesterase or red blood cell [RBC] 

acetylcholinesterase) and plasma cholinesterase (PChE—also referred to as butrylcholinesterase, serum 

cholinesterase, or pseudocholinesterase), producing acetic acid and thiocholine. Thiocholine reacts with 

the Ellman reagent dithionitrobenzoic acid (DTNB) to produce the anion of 5-thio-2-nitrobenzoic acid, 

which forms a yellow color that is measured spectrophotometrically at 412 nm. The rate of color 

formation is proportional to the amount of either AChE or PChE. An adaptation of the Ellman assay is a 

microtiter assay method for AChE that has been developed by Doctor et al. (1987). The AChE samples to 

be assayed are added to microtiter plates and enzymatic hydrolysis is initiated by adding Ellman reaction 

mixture (DTNB). The hydrolysis reaction is terminated by the addition of an AChE inhibitor 

(1,5-bis(4-allyldimethylammoniumphenyl)-pentan-3-one dibromide. The absorbance of the microtiter is 

measured continuously at 405 nm. 

An automated version of the Ellman assay has been implemented by the state of California to detect 

exposure to organophosphate pesticides in field workers (Knaack et al. 1978). Samples of whole blood 

and plasma are diluted with tris(hydroxymethyl)aminomethane (0.05 Molar) and sodium chloride 

(0.114 Molar) buffer adjusted to pH 7.7 with hydrogen chloride. The samples are centrifuged at 

1,600 rpm for 4 minutes to separate red blood cells from plasma, which are then analyzed for esterase 

activity using a continuous flow Technicon Analyzer. Prediluted whole blood or plasma samples are 

passed through a 37 °C dry bath incubator for approximately 1 minute. The sample is then passed 

through a 12-inch dialyzer equipped with a Type C membrane and the released thiocholine is passed 

through a solution of DTNB. The thiocholine DTNB mixture is sent to a delay coil for color development 

prior to being passed through a 15x1.5 mm flow cell. 

Methods for analyzing guthion in biological samples are shown in Table 7-1. 
GUTHION 147 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Guthion and Various Metabolites 

in Biological Samples 

Sample 

matrix Preparation method 

Analytical 

method 

Sample detection 

limit 

Percent 

recovery Reference 

Human 

blood 

Solid-phase extraction 

(SPE) with C18 cartridge 

followed by elution with 

MTBE 

GC/NPD 10 μg/L 119–121 Pitarch et al. 2001 

Human Collection of blood UV absorbance No data No data Ellman et al. 1961 

blood samples, addition of 

0.1 M phosphate buffer 

(pH=8.0) and DTNB 

(at 410–412 nm) 

Urine SPE with C18 cartridge 

followed by elution with 

MTBE 

GC/NPD 1.7 μg/L 96–107 Pitarch et al. 2001 

Urine LLME using 

dichloromethane 

GC/NPD 6.0 μg/L 98–109 Pitarch et al. 2001 

Urine Solid-phase extraction, 

followed by 

derivitization with PFBB 

GC/FPD 7.4 μg/L (DMP) 

1.1 μg/L (DMTP) 

0.7 μg/L (DMDTP) 

85–137 Koch et al. 2002 

Urine Solid-phase extraction, 

followed by 

derivitization with PFBB 

GC/FPD 15 μg/L (DMTP) 

13 μg/L(DMDTP) 

47–116 Loewenherz et al. 

1997 

DMDTP = dimethyl dithiophosphate; DMP = dimethyl phosphate; DMTP = dimethyl thiophosphate; 

DTNB = dithionitrobenzoic acid (Ellman reagent); FPD = flame photometric detector; GC = gas chromatography; 

LLME = liquid-liquid microextraction; MTBE = methyl t-butyl ether; NPD = nitrogen phosphorous detector; 

PFBB = pentafluorobenzylbromide; SPE = solid-phase extraction; UV = ultraviolet 
GUTHION 148 

7. ANALYTICAL METHODS 

7.2 ENVIRONMENTAL SAMPLES 

The detection and analysis of guthion in environmental samples is routinely accomplished by GC/NPD, 

GC/FPD and GC/MS techniques. Organophosphate pesticides such as guthion may also be detected by 

the electron capture detector; however, the GC/ECD is not as specific as the NPD or FPD (EPA 2000b). 

Like most organophosphate pesticides, guthion is subject to hydrolysis under alkaline conditions; 

therefore, care must be exercised during the extraction and storage process in order to avoid hydrolytic 

degradation. Aqueous extraction is usually performed at neutral pH with methylene chloride using 

separatory funnel techniques such as EPA Method 3510 (EPA 1996a). Solid samples may be extracted 

with hexane-acetone (1:1) or methylene chloride-acetone (1:1) using Method 3540 (Soxhlet extraction) 

(EPA 1996b), Method 3541 (automated Soxhlet extraction) (EPA 1994a), Method 3545 (pressurized fluid 

extraction) (EPA 1998a), Method 3546 (microwave extraction) (EPA 2000a), or other appropriate 

technique. Method 3550 (ultrasonic extraction) is not as rigorous as other extraction methods for 

soils/solids, and EPA has not yet validated this technique for organophosphate pesticides (EPA 1996c). 

Storage is maintained under dark conditions at 4 °C in order to minimize biotic and abiotic degradation. 

Extraction is usually performed within 7 days of sample collection and analysis should begin within 

40 days of extraction. Cleanup procedures using Florisil, silica gel, size exclusion chromatography, or 

some other appropriate method is usually required to remove various contaminants found in 

environmental matrices. Detection limits in water and soil are 0.10 μg/L and 5 μg/kg, respectively, using 

EPA Method 8141B (GC/FPD) (EPA 2000b). Method 8270D is a GC/MS method used for the detection 

of guthion in groundwater and has a detection limit of 100 μg/L (EPA 1998b). Air samples can be 

analyzed for the presence of guthion by GC/FPD as described by NIOSH Method 5600 (NIOSH 1994). 

The detection limit for this method is approximately 0.0012 mg/m3

. 

Several analytical methods have been published in the open literature that summarize the analysis of 

guthion in environmental samples including fruits/foods/juices (Danis et al. 2002; Kyriakidis et al. 2001; 

Sheridan and Meola 1999). Using GC coupled with flame thermionic detectors (FTD) or MS detectors, 

Danis et al. (2002) demonstrated guthion detection limits in the low μg/kg range for fresh and canned 

peaches. Recoveries in spiked samples were essentially 100% using an SPE method with nonporous 

carbon-based packing (Danis et al. 2002). GC with ion trap tandem MS/MS was used to detect guthion 

and other pesticides at the parts per billion (ppb) levels in fruits, vegetables, and milk (Sheridan and 

Meola 1999). GC/NPD was used to detect guthion in peach and orange juice (Kyriakidis et al. 2001). 

Household or vehicular dust samples are analyzed for the presence of guthion using solvent extraction 
GUTHION 149 

7. ANALYTICAL METHODS 

followed by size exclusion chromatography and analysis by GC/MS (Moate et al. 2002; Simcox et al. 

1995). 

Methods for analyzing guthion in environmental samples are shown in Table 7-2. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of guthion is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of guthion. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. The most specific biomarkers for exposure to guthion are the parent compound itself and 

metabolites in body fluids. However, because guthion is rapidly metabolized and eliminated (see 

Section 3.4), the parent compound may only be found in cases of acute exposure to considerable amounts 

of the pesticide (Pitarch et al. 2001). Although an analytical method has been described for determining 

the level of guthion in blood and urine (Pitarch et al. 2001), exposure is usually analyzed by measuring 

the level of urinary metabolites DMP, DMTP, and DMDTP. Methods exist that can measure background 

levels as well as levels at which biological effects might occur for these metabolites in urine by GC or 

GC/MS (Koch et al. 2002; Loewenherz et al. 1997). These three metabolites are not specific to guthion, 

and may be present due to exposure to other organophosphates. A biomarker of exposure specific to 

guthion is needed. 
GUTHION 150 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Guthion in 

Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Air Collection on sorbent filter 

with a sampling flow rate 

of 0.2–1.0 L/minute. 

Extraction with 

toluene/acetone (9:1) 

Air Collection with high 

volume sampler followed 

by extraction with ethyl 

acetate/hexane 

Water Sepratory funnel 

extraction with methylene 

chloride at neutral pH 

Groundwater Sepratory funnel 

extraction with methylene 

chloride at neutral pH 

Soil Extraction with hexaneacetone (1:1) or 

methylene chlorideacetone (1:1), cleanup 

with Florisil, silica gel, size 

exclusion chromatography, or sulfur 

Soil Extraction with acetone/ 

dichloromethane (1:1) 

Soil Ultrasonic sonication with 

acetone. Separation with 

hexane and water 

followed by drying with 

anhydrous sodium sulfate 

Dust Sieve samples to remove 

debris followed by 

acetone extraction and 

cleanup with size 

exclusion chromatography 

Dust Collection with high 

volume surface sampler, 

sieve samples through 

mesh to remove debris, 

followed by extraction with 

acetone 

Sediment Soxhlet extraction in 

hexane/acetone 

Sediment Soxhlet extraction in 

acetone/dichloromethane 

GC/FPD 0.0012 mg/m3 97 NIOSH 1994 

GC/MS SIM No data 76 Foreman et al. 

2000 

GC/FPD 0.10 μg/L 101–126 EPA 2000b 

(Method 8141) 

GC/MS 100 μg/L No data EPA 1998b 

(Method 8270) 

GC/FPD 5 μg/kg 87–156 EPA 2000b 

(Method 8141) 

GC/FPD 10 μg/kg No data Gamon et al. 

2003 

GC/MS SIM 32 μg/kg 90 Simcox et al. 

1995 

GC/MS 55 μg/kg 62–81 (house Moate et al. 

dust); 81.4– 2002 

106 (vehicle 

dust) 

GC/MS SIM 40 μg/kg 77 Simcox et al. 

1995 

GC/MS SIM 14 μg/kg 70–100 Villa S et al. 

2003 

GC/ECD 0.20 μg/kg 96 Knuth et al. 

2000 
GUTHION 151 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Guthion in 

Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Fruit Homogenization followed GC/FTD; 8 μg/kg 100–105 Danis et al. 

(peaches) by extraction with GC/MS (GC/FTD); 2002 

acetonitrile/toluene (3:1) 12 μg/kg 

(GC/MS) 

Fruit, Homogenization followed GC/MS/MS ppb range No data Sheridan and 

vegetables, by extraction with Meola 1999 

milk acetonitrile/ethanol (95:5) 

Apples Homogenization and GC/MS 0.022 μg/kg 84 Rawn et al. 

extraction with 2006 

acetone/hexane (5:1), 

followed by cleanup with 

gel permeation 

chromatography and 

Florisil 

Fruit juice Extraction with ethyl GC/NPD 0.004 mg/kg 87– Kyriakidis et al. 

acetate and sodium 110 (orange 2001 

sulphate, followed by juice); 92– 

filtration with 108 (peach 

No. 1 Whatman filter juice) 

paper 

Fish and Homogenized samples GC/FPD 0.20 μg/kg 105 (fish); Knuth et al. 

macrophytes were extracted with (fish); 86 (macro- 2000 

acetone/dichloroethane 0.22 μg/kg phyte) 

(macrophyte) 

ECD = electron capture detector; FPD = flame photometric detector; FTD = flame thermionic detector; GC = gas 

chromatography; MS = mass spectrometry; NPD = nitrogen phosphorous detector; SIM = selected ion monitoring 
GUTHION 152 

7. ANALYTICAL METHODS 

Effect. Guthion causes toxic effects in humans through the inhibition of acetylcholinesterase, thereby 

resulting in a buildup of acetylcholine at the neuromuscular junction and affecting neuromuscular 

transmission. Diagnosis of organophosphate poisoning, including guthion, can be made by the presence 

of characteristic clinical signs and measurements of serum (plasma) cholinesterase and RBC 

acetylcholinesterase activities. Enzyme inhibition, however, is not specific for organophosphates since 

exposure to carbamate insecticides also results in cholinesterase inhibition. Nonspecific cholinesterase 

(pseudocholinesterase, butyrylcholinesterase) is present in myelin, liver, and plasma, whereas 

acetylcholinesterase is present in the central and peripheral nervous systems and in RBC. A spectroscopic 

method exists which can measure the depression of cholinesterase activity (Ellman et al. 1961). 

Erythrocyte acetylcholinesterase or AChE and plasma butrylcholinesterase or PChE are both measured to 

diagnose exposure to organophosphates; however, it is believed that AChE is a more accurate test of 

synaptic acetylcholinesterase (Tafuri and Roberts 1987). The PChE measurement determines the 

pseudocholinesterase activity in the liver, which may be depressed by factors other than organophosphate 

exposure such as liver disease caused by cirrhosis or hepatitis. In addition, normal cholinesterase values 

vary widely in the human population, and a person with baseline activity near the upper limit of normal 

could be exposed to organophosphates and still have a reading within normal limits (Midtling et al. 1985; 

Tafuri and Roberts 1987). Thus, one data need is the development of markers specific to guthion, which 

enable early and reliable detection of systemic responses and health effects arising from such exposures. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods for determining guthion levels in air (Foreman et al. 2000; NIOSH 1994), water (EPA 

1998b, 2000b), soil (EPA 2000b; Gamon et al. 2003), sediment (Knuth et al. 2000; Villa et al. 2003), and 

various foods (Danis et al. 2002; Kyriakidis et al. 2001; Sheridan and Meola 1999) exist. These methods 

provide well-tested, reliable, and sensitive means for the analysis of guthion in environmental media. 

These methods are sensitive enough for measuring background levels and levels at which adverse health 

effects might occur. No additional analytical methods for determining low levels of guthion in 

environmental media are needed at this time. 

7.3.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2006) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs pertinent to the analysis of guthion in 

biological or environmental samples. Researchers at the University of Maine Laboratory for Surface 
GUTHION 153 

7. ANALYTICAL METHODS 

Science and Technology Center are developing an organophosphate pesticide vapor sensor and testing the 

feasibility of using this sensor to detect residues of two pesticides (guthion and phosmet) on blueberries. 
GUTHION 154 

7. ANALYTICAL METHODS 

This page is intentionally blank. 
GUTHION 155 

8. REGULATIONS AND ADVISORIES 

ATSDR has derived an acute-duration inhalation MRL of 0.02 mg/m3

 for guthion based on a NOAEL of 

1.24 mg/m3

 for significant reductions in erythrocyte AChE activity in male rats exposed to guthion 

aerosols 6 hours/day, 5 days/week for 2 weeks (Kimmerle 1976). The MRL was derived by dividing the 

NOAEL[HEC] of 0.50 mg/m3

 by an uncertainty factor of 30 (3 for extrapolation from animals to humans 

using dosimetric adjustment and 10 for human variability). 

ATSDR has derived an intermediate-duration inhalation MRL of 0.01 mg/m3

 for guthion based on a 

NOAEL of 1.24 mg/m3

 for significant reductions in erythrocyte AChE activity in male and female rats 

exposed to guthion aerosols 6 hours/day, 5 days/week for 12 weeks (Kimmerle 1976). The MRL was 

derived by dividing the NOAEL[HEC] of 0.37 mg/m3

 by an uncertainty factor of 30 (3 for extrapolation 

from animals to humans using dosimetric adjustment and 10 for human variability). 

The intermediate-duration inhalation MRL of 0.01 mg/m3

 was adopted for use as the chronic-duration 

inhalation MRL. 

ATSDR has derived an acute-duration oral MRL of 0.01 mg/kg/day for guthion. The MRL is based on a 

BMDL of 1.04 mg/kg/day for inhibition of erythrocyte AChE activity in pregnant rats administered 

guthion by gavage on gestation days 6–15 (Astroff and Young 1998) and an uncertainty factor of 

100 (10 for extrapolation from animals to humans and 10 for human variability). 

ATSDR has derived an intermediate-duration oral MRL of 0.003 mg/kg/day for guthion. The MRL is 

based on a BMDL of 0.29 mg/kg/day for inhibition of erythrocyte AChE activity in dogs exposed to 

guthion in the diet for 26 weeks (Allen et al. 1990) and an uncertainty factor of 100 (10 for extrapolation 

from animals to humans and 10 for human variability). 

ATSDR has derived a chronic-duration oral MRL of 0.003 mg/kg/day for guthion. The MRL is based on 

a BMDL of 0.30 mg/kg/day for inhibition of erythrocyte AChE activity in dogs exposed to guthion in the 

diet for 52 weeks (Allen et al. 1990) and an uncertainty factor of 100 (10 for extrapolation from animals 

to humans and 10 for human variability). 

EPA has not derived an inhalation reference concentration (RfC) or an oral reference dose (RfD) for 

guthion. 

***DRAFT – DO NOT CITE OR QUOTE – October 1, 2008*** Version 1.0 
GUTHION 156 

8. REGULATIONS AND ADVISORIES 

The EPA Office of Pesticide Programs calculated an acute oral reference value of 0.003 mg/kg/day based 

on a LOAEL of 1.0 mg/kg/day from an acute neurotoxicity study in rats in which inhibition of plasma 

ChE and erythrocyte and brain AChE activities were observed (EPA 2001b). The uncertainty factor used 

in this assessment was 300 (10 for interspecies extrapolation, 10 for intraspecies variation, and 3 for the 

use of a LOAEL). 

The EPA Office of Pesticide Programs calculated a chronic oral reference value 0.00149 mg/kg/day based 

on a NOAEL of 0.149 mg/kg/day from a 1-year chronic toxicity study in dogs in which erythrocyte 

AChE inhibition was observed (EPA 2001b). The uncertainty factor used in this assessment was 

100 (10 for interspecies variation and 10 for intraspecies variation). 

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), tolerances for residues on raw 

agricultural commodities for guthion range from 0.2 to 5 ppm (EPA 2006i); see 40 CFR 180.154 for a 

complete listing of tolerances for residues and the corresponding raw agricultural commodities. EPA has 

further upheld these tolerances for residues in an order denying objections from the Natural Resource 

Defense Council (NRDC) to the issuance of these tolerances (EPA 2004b). Guthion is a pesticide 

classified for restricted use and is limited to use by or under the direct supervision of a certified applicator 

(EPA 2006e). 

Guthion is currently registered for use on the following crops (EPA 1999a): almonds; apples/crabapples; 

blueberries, lowbush and highbush; Brussels sprouts; cherries, sweet and tart; nursery stock; parsley; 

pears; pistachios; and walnuts. On June 9, 2006, EPA proposed the cancellation of guthion usage for 

apples, blueberries, cherries, parsley, and pears by 2010 and a phase out of its uses on almonds, Brussels 

sprouts, pistachios, walnuts, and nursery stock by 2007 (EPA 2006l). 

The international and national regulations and guidelines regarding guthion in air, water, and other media 

are summarized in Table 8-1. 
GUTHION 157 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Guthion 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No data IARC 2007 

WHO Air quality guidelines No data WHO 2000 

Drinking water quality guidelines No data WHO 2004 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA)a,b,c 0.2 mg/m3

 ACGIH 2007 

EPA AEGL No data EPA 2006a 

Hazardous air pollutant No data EPA 2006c 

42 USC 7412 

NIOSH 

OSHA 

REL (10-hour TWA)d

 IDLH 

PEL (8-hour TWA) for general industrye

 0.2 mg/m3

10 mg/m3 

 0.2 mg/m3

NIOSH 2005 

 OSHA 2005c 

29 CFR 1910.1000 

PEL (8-hour TWA) for construction 

industrye 

0.2 mg/m3

 OSHA 2005b 

29 CFR 1926.55, 

PEL (8-hour TWA) for shipyard industrye

 0.2 mg/m3

Appendix A 

 OSHA 2005a 

29 CFR 1915.1000 

b. Water 

DOT Marine pollutant Yes DOT 2005 

49 CFR 172.101, 

Appendix B 

EPA Designated as hazardous substances in Yes EPA 2006b 

accordance with Section 311(b)(2)(A) of 40 CFR 116.4 

the Clean Water Act 

Drinking water standards and health No data EPA 2006m 

advisories 

National primary drinking water standards No data EPA 2003 

Reportable quantities of hazardous 1 pound EPA 2006f 

substances designated pursuant to 40 CFR 117.3 

Section 311 of the Clean Water Act 

Water quality criteria for nonpriority EPA 2006d 

pollutants 

Fresh water (CCC) 0.01 μg/L 

Salt water (CCC) 0.01 μg/L 

c. Food 

EPA Tolerances for residues (see Range: 0.2–5 ppm EPA 2006i 

40 CFR 180.154 for a complete listing of 40 CFR 180.154 

tolerances for residues on raw agricultural 

commodities) 
GUTHION 158 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Guthion 

Agency Description Information Reference 

NATIONAL (cont.) 

FDA Order denying objections to issuance of 

tolerance 

Yes EPA 2004b 

69 FR 30042 

Bottled drinking water No data FDA 2005 

21 CFR 165.110 

d. Other 

 ACGIH 

EPA 

Carcinogenicity classification 

Biological exposure indices (for acetylcholinesterase inhibiting pesticides) 

Cholinesterase activity in red blood 

cells (sampling time is discretionary) 

Carcinogenicity classification 

RfC 

A4f 

70% of individual’s 

baseline 

No data 

No data 

ACGIH 2007

 RfD No data 

Pesticide classified for restricted useg All liquids with a concentration >13.5% 

EPA 2006e 

40 CFR 152.175 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous 

substance 

Yes EPA 2006g 

40 CFR 302.4 

DHHS 

Reportable quantity 

Extremely hazardous substances and 

their threshold planning quantities 

Carcinogenicity classification 

1 pound 

10/10,000 pounds 

No data 

EPA 2006h 

40 CFR 355, 

Appendix A 

NTP 2004 

a

Inhalable fraction and vapor b

Skin notation: refers to the potential significant contribution to the overall exposure by the cutaneous route, 

including mucous membranes and the eyes, either by contact with vapors, liquids, and solids. c

Sensitization: refers to the potential for an agent to produce sensitization, as confirmed by human or animal data. d

Skin designation: indicates the potential for dermal absorption; skin exposure should be prevented as necessary

through the use of good work practices, gloves, coveralls, goggles, and other appropriate equipment. e

Skin designation f

A4: not classifiable as a human carcinogen g

Pesticide classified as restricted use: limited to use by or under the direct supervision of a certified applicator for 

agricultural crop uses. Criteria influencing restriction includes inhalation hazard to humans. 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = Acute Exposure Guideline Level; 

CCC = Criterion Continuous Concentration; CERCLA = Comprehensive Environmental Response, Compensation, 

and Liability Act; CFR = Code of Federal Regulations; DHHS = Department of Health and Human Services; 

DOT = Department of Transportation; EPA = Environmental Protection Agency; FDA = Food and Drug 

Administration; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or 

health; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; REL = recommended 

exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; STEL = short-term exposure 

limit; TLV = threshold limit values; TWA = time-weighted average; USC = United States Code; WHO = World Health 

Organization 
______________________ 

GUTHION 159 

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GUTHION 177 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 
GUTHION 178 

10. GLOSSARY 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 
GUTHION 179 

10. GLOSSARY 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 
GUTHION 180 

10. GLOSSARY 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 
GUTHION 181 

10. GLOSSARY 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 
GUTHION 182 

10. GLOSSARY 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 
GUTHION A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 
GUTHION A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 
GUTHION A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Guthion 

CAS Numbers: 86-50-0 

Date: June 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 3 

Species: Rat 

Minimal Risk Level: 0.02 [ ] mg/kg/day [ ] ppm [X] mg/m3 

Reference: Kimmerle G. 1976. Subchronic inhalation toxicity of azinphos-methyl in rats. Arch Toxicol 

35:83-89. 

Experimental design: In this study (Kimmerle 1976), groups of 10 male and 10 female SPF Wistar rats 

were exposed to aerosolized guthion at 0.195, 1.24, or 4.72 mg/m3

, 6 hours/day, 5 days/week for 

12 weeks. Guthion aerosols were generated by first dissolving technical-grade guthion in a 1:1 solution 

of ethanol/polypropylene glycol. Ninety-seven percent of the droplets had a diameter of 1±0.5 μm. The 

animals were inspected daily and weighed weekly. Erythrocyte AChE and plasma ChE activities were 

determined after 2, 4, 6, 8, 10, and 12 weeks and determinations of hematology, serum glutamicoxalacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatase, 

urea, creatinine, and bilirubin were conducted after 12 weeks of exposure. At study termination, animals 

were sacrificed for gross examination. The thyroid, thymus, heart, lungs, liver, spleen, kidneys, adrenals, 

and gonads were weighed and examined histologically and brain AChE activity was determined. 

Effect noted in study and corresponding doses: There were no significant changes in appearance or 

behavior of male or female rats. Male rats in the 4.72 mg/m3

 group showed a 20% reduction in body 

weight gain during the 12-week exposure period. Although body weight was not reported on week 2, on 

week 4, body weight gain in male rats in the 4.72 mg/m3

 group was 60% that in control animals. After 

2 weeks of exposure, erythrocyte AChE activity was reduced by 25 and 18% in male and female rats, 

respectively, in the 4.72 mg/m3

 group, but not at lower concentrations. There were no biologically 

significant reductions in plasma ChE activity at any of the doses tested. 

Dose and end point used for MRL derivation: The MRL is based on a NOAEL of 1.24 mg/m3

 and a 

LOAEL of 4.72 mg/m3 for decreased erythrocyte AChE activity after 2 weeks of exposure. 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustments 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: As 

per MRL guidance from ATSDR, a 5–7-day duration adjustment is not conducted for acute inhalation 
GUTHION A-4 

APPENDIX A 

exposures. Thus, the NOAEL of 1.24 mg/m3 was adjusted for intermittent exposure (NOAEL[ADJ]) as 

follows: 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours 

NOAEL[ADJ] = 0.31 mg/m3 

The human equivalent concentration (HEC) of the NOAEL[ADJ] was calculated using the equations below. 

The RDDR[ER] is the regionally deposited dose ratio for the extrarespiratory effects. It is calculated using 

EPA’s software (version 2.3) for calculating RDDRs (EPA 1994b) and particle size and body weight data 

from Kimmerle (1976). A presentation of the equations and assumptions used to calculate the RDDR can 

be found in EPA (1994b). 

NOAEL[HEC] = NOAEL[ADJ] x RDDR[ER] 

NOAEL[HEC] = 0.31 mg/m3

 x 1.626 

NOAEL[HEC] = 0.50 mg/m3 

An RDDRER of 1.626 was estimated using the default parameters and body weight data presented in 

Table A-1. 

Table A-1. Default Parameters Used in the Derivation of RDDRER 

Parameter Humans Rats 

Body weight (kg) 70.00 0.182a 

Minute volume (L) 

ET area (cm2

)

b

TB area (cm2

)

c

PU area (m2

)

d

13.80 

200.00 

3,200.00 

54.00 

0.139 

15.00 

22.50 

0.34 

a

2-week body weight value estimated from Kimmerle (1976) b

Extrathoracic respiratory tract region c

Tracheobronchial respiratory tract region d

Pulmonary respiratory tract region 

RDDRER = regionally deposited dose ratio for the extrarespiratory effects 

Based on the information provided by Kimmerle (1976) it was assumed that the sizes of the aerosol 

particles were log-normally distributed in a manner such that 1.5% of these were <0.5 μm and 1.5% were 

>1.5 μm. Based on these assumptions, a geometric mean and geometric standard deviation of 0.9 and 

0.23 μm, respectively, were calculated. These values were used to calculate a Mass Median Aerodynamic 

Diameter (MMAD) of 0.88 μm using the recommended equation in Table H-2 (shown below) of the 

guidance document Methods for Derivation of Inhalation Reference Concentrations and Application of 

Inhalation Dosimetry (EPA 1994b). 

MMAD = CMAD e(3[ln variance]

2

) 

No conversion is required for the geometric standard deviation and the geometric standard deviation of 

0.23 was used. CMAD is the count median aerodynamic diameter (0.9 μm). 

The NOAEL[HEC] of 0.50 mg/m3

 was divided by an uncertainty factor of 30 (3 for extrapolation from 

animals to humans using dosimetric adjustment and 10 for human variability), resulting in an acute­
GUTHION A-5 

APPENDIX A 

duration inhalation MRL of 0.02 mg/m3. Application of the benchmark dose methodology to the data 

from Kimmerle (1976) was considered, but the data were presented as means without standard errors or 

standard deviations. Without these measures, the benchmark dose methodology could not be applied. 

Was a conversion used from intermittent to continuous exposure? Yes, animals were exposed 

6 hours/day, 5 days/week. 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours 

NOAEL[ADJ] = 0.31 mg/m3 

Other additional studies or pertinent information that lend support to this MRL: EPA (1978a) reported a 

41% (range 27–59%) reduction in blood ChE activity in rats exposed to guthion aerosols (39 mg/m3

) for 

1 hour. The consistent observation of reduced ChE activity in the two available inhalation studies is in 

agreement with the observations made in a number of studies with guthion administered orally to rats and 

dogs during acute (Astroff and Young 1998; Pasquet et al. 1976), intermediate (Holzum 1990; Sheets et 

al. 1997), and chronic (Allen et al. 1990; Schmidt and Chevalier 1984) exposures. 

Agency Contacts (Chemical Managers): Nickolette Roney, Selene Chou, Yee-Wan Stevens 
GUTHION A-6 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Guthion 

CAS Numbers: 86-50-0 

Date: June 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 7 

Species: Rat 

Minimal Risk Level: 0.01 [ ] mg/kg/day [ ] ppm [X] mg/m3 

Reference: Kimmerle G. 1976. Subchronic inhalation toxicity of azinphos-methyl in rats. Arch Toxicol 

35:83-89. 

Experimental design: In this study (Kimmerle 1976), groups of 10 male and 10 female SPF Wistar rats 

were exposed to aerosolized guthion at 0.195, 1.24, or 4.72 mg/m3

, 6 hours/day, 5 days/week for 

12 weeks. Guthion aerosols were generated by first dissolving technical-grade guthion in a 1:1 solution 

of ethanol/polypropylene glycol. Ninety-seven percent of the droplets had a diameter of 1±0.5 μm 

(Kimmerle 1976). The animals were inspected daily and weighed weekly. Erythrocyte AChE and 

plasma ChE activities were determined after 2, 4, 6, 8, 10, and 12 weeks and determinations of 

hematology, SGOT, SGPT, alkaline phosphatase, urea, creatinine, and bilirubin were conducted after 

12 weeks of exposure. At study termination, animals were sacrificed for gross examination. The thyroid, 

thymus, heart, lungs, liver, spleen, kidneys, adrenals, and gonads were weighed and examined 

histologically and brain AChE activity was determined. 

Effect noted in study and corresponding doses: There were no significant changes in appearance or 

behavior of male or female rats. Male rats in the 4.72 mg/m3

 group showed a 20% reduction in body 

weight gain during the 12-week exposure period. No effects were detected in the examined 

hematological and serum clinical chemistry parameters. There were no observed differences in absolute 

or relative organ weights or morphological alterations in organs or tissues in any of the rats. From week 

4 to week 12, erythrocyte AChE activity was reduced by 29–48% in male and 26–39% in female rats in 

the 4.72 mg/m3

 group. There were no additional reductions in erythrocyte AChE activity beyond week 4. 

Reductions in erythrocyte AChE activity in rats exposed to guthion doses <4.72 mg/m3

 were 17% or less 

and are not considered an adverse effect. The investigator noted that brain ChE activity was not reduced 

at any of the concentrations tested, but no data were shown. 

Dose and end point used for MRL derivation: The MRL is based on a NOAEL of 1.24 mg/m3

 and 

LOAEL of 4.72 mg/m3

 for decreased erythrocyte AChE activity. 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustments 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 
GUTHION A-7 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The 

NOAEL of 1.24 mg/m3

 was adjusted for intermittent exposure (NOAEL[ADJ]) as follows: 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours x 5 days/7 days

 NOAEL[ADJ] = 0.22 mg/m3 

The human equivalent concentration (HEC) of the NOAEL[ADJ] was calculated using the equations below. 

The RDDR[ER] is the regionally deposited dose ratio for the extrarespiratory effects. It is calculated using 

EPA’s software (version 2.3) for calculating RDDRs (EPA 1994b) and particle size and body weight data 

from Kimmerle (1976). A presentation of the equations and assumptions used to calculate the RDDR can 

be found in EPA (1994b). 

NOAEL[HEC] = NOAEL[ADJ] x RDDR[ER] 

NOAEL[HEC] = 0.22 mg/m3

 x 1.695 

NOAEL[HEC] = 0.37 mg/m3 

An RDDRER of 1.695 was estimated using the default parameters and body weight data presented in 

Table A-2. 

Table A-2. Default Parameters Used in the Derivation of RDDRER 

Parameter Humans Rats 

Body weight (kg) 70.00 0.253a 

Minute volume (L) 

ET area (cm2

)

b

TB area (cm2

)

c

PU area (m2

)

d

13.80 

200.00 

3,200.00 

54.00 

0.182 

15.00 

22.50 

0.34 

a

12-week body weight value from Kimmerle (1976) b

Extrathoracic respiratory tract region c

Tracheobronchial respiratory tract region d

Pulmonary respiratory tract region 

RDDRER = regionally deposited dose ratio for the extrarespiratory effects 

Based on the information provided by Kimmerle (1976), it was assumed that the sizes of the aerosol 

particles were log-normally distributed in a manner such that 1.5% of these were <0.5 μm and 1.5% were 

>1.5 μm. Based on these assumptions, a geometric mean and geometric standard deviation of 0.9 and 

0.23 μm, respectively, were calculated. These values were used to calculate a MMAD of 0.88 μm using 

the recommended equation in Table H-2 of the guidance document Methods for Derivation of Inhalation 

Reference Concentrations and Application of Inhalation Dosimetry (EPA 1994b). 

MMAD = CMAD e(3[ln variance]

2

) 

No conversion is required for the geometric standard deviation and the geometric standard deviation of 

0.23 was used. CMAD is the count median aerodynamic diameter (0.9 μm). 

The NOAEL[HEC] of 0.37 mg/m3

 was divided by an uncertainty factor of 30 (3 for extrapolation from 

animals to humans using dosimetric adjustment and 10 for human variability), resulting in an 

intermediate-duration inhalation MRL of 0.01 mg/m3

. Application of the benchmark dose methodology 
GUTHION A-8 

APPENDIX A 

to the data from Kimmerle (1976) was considered, but the data were presented as means without standard 

errors or standard deviations. Without these measures, the benchmark dose methodology could not be 

applied. 

Was a conversion used from intermittent to continuous exposure? Yes, animals were exposed 

6 hours/day, 5 days/week. 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours x 5 days/7 days 

NOAEL[ADJ] = 0.22 mg/m3 

Other additional studies or pertinent information that lend support to this MRL: EPA (1978a) reported a 

41% (range 27–59%) reduction in blood ChE activity in rats exposed to guthion aerosols (39 mg/m3

) for 

1 hour. The consistent observation of reduced ChE activity in the two available inhalation studies is in 

agreement with the observations made in a number of studies with guthion administered orally to rats and 

dogs during acute (Astroff and Young 1998; Pasquet et al. 1976), intermediate (Holzum 1990; Sheets et 

al. 1997), and chronic (Allen et al. 1990; Schmidt and Chevalier 1984) exposures. 

Agency Contacts (Chemical Managers): Nickolette Roney, Selene Chou, Yee-Wan Stevens 
GUTHION A-9 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Guthion 

CAS Numbers: 86-50-0 

Date: June 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 7 

Species: Rat 

Minimal Risk Level: 0.01 [ ] mg/kg/day [ ] ppm [X] mg/m3 

Reference: Kimmerle G. 1976. Subchronic inhalation toxicity of azinphos-methyl in rats. Arch Toxicol 

35:83-89. 

Experimental design: In this study (Kimmerle 1976), groups of 10 male and 10 female SPF Wistar rats 

were exposed to aerosolized guthion at 0.195, 1.24, or 4.72 mg/m3

, 6 hours/day, 5 days/week for 

12 weeks. Guthion aerosols were generated by first dissolving technical-grade guthion in a 1:1 solution 

of ethanol/polypropylene glycol. Ninety-seven percent of the droplets had a diameter of 1±0.5 μm 

(Kimmerle 1976). The animals were inspected daily and weighed weekly. Erythrocyte AChE and 

plasma ChE activities were determined after 2, 4, 6, 8, 10, and 12 weeks and determinations of 

hematology, SGOT, SGPT, alkaline phosphatase, urea, creatinine, and bilirubin were conducted after 

12 weeks of exposure. At study termination, animals were sacrificed for gross examination. The thyroid, 

thymus, heart, lungs, liver, spleen, kidneys, adrenals, and gonads were weighed and examined 

histologically and brain AChE activity was determined. 

Effect noted in study and corresponding doses: There were no significant changes in appearance or 

behavior of male or female rats. Male rats in the 4.72 mg/m3

 group showed a 20% reduction in body 

weight gain during the 12-week exposure period. No effects were detected in the examined 

hematological and serum clinical chemistry parameters. There were no observed differences in absolute 

or relative organ weights or morphological alterations in organs or tissues in any of the rats. From week 

4 to week 12, erythrocyte AChE activity was reduced by 29–48% in male and 26–39% in female rats in 

the 4.72 mg/m3

 group. Reductions in erythrocyte AChE activity in rats exposed to guthion doses 

<4.72 mg/m3

 were 17% or less and are not considered an adverse effect. The investigator noted that brain 

AChE activity was not reduced at any of the concentrations tested, but no data were shown. 

Dose and end point used for MRL derivation: The MRL is based on a NOAEL of 1.24 mg/m3

 and 

LOAEL of 4.72 mg/m3

 for decreased erythrocyte AChE activity. 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X ] 3 for extrapolation from animals to humans 

[X ] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 
GUTHION A-10 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The 

NOAEL of 1.24 mg/m3

 was adjusted for intermittent exposure (NOAEL[ADJ]) as follows: 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours x 5 days/7 days

 NOAEL[ADJ] = 0.22 mg/m3 

The human equivalent concentration (HEC) of the NOAEL[ADJ] was calculated using the equations below. 

The RDDR[ER] is the regionally deposited dose ratio for the extrarespiratory effects. It is calculated using 

EPA’s software (version 2.3) for calculating RDDRs (EPA 1994b) and particle size and body weight data 

from Kimmerle (1976). 

NOAEL[HEC] = NOAEL[ADJ] x RDDR[ER] 

NOAEL[HEC] = 0.22 mg/m3 x 1.695 

NOAEL[HEC] = 0.37 mg/m3 

An RDDRER of 1.695 was estimated using the default parameters and body weight data presented in 

Table A-3. 

Table A-3. Default Parameters Used in the Derivation of RDDRER 

Parameter Humans Rats 

Body weight (kg) 70.00 0.253a 

Minute volume (L) 

ET area (cm2

)

b

TB area (cm2

)

c

PU area (m2

)

d

13.80 

200.00 

3,200.00 

54.00 

0.182 

15.00 

22.50 

0.34 

a

12-week body weight value from Kimmerle (1976) b

Extrathoracic respiratory tract region c

Tracheobronchial respiratory tract region d

Pulmonary respiratory tract region 

RDDRER = regionally deposited dose ratio for the extrarespiratory effects 

Based on the information provided by Kimmerle (1976), it was assumed that the sizes of the aerosol 

particles were log-normally distributed in a manner such that 1.5% of these were <0.5 μm and 1.5% were 

>1.5 μm. Based on these assumptions, a geometric mean and geometric standard deviation of 0.9 and 

0.23 μm, respectively, were calculated. These values were used to calculate a MMAD of 0.88 μm using 

the recommended equation in Table H-2 of the guidance document Methods for Derivation of Inhalation 

Reference Concentrations and Application of Inhalation Dosimetry (EPA 1994b). 

MMAD = CMAD e(3[ln variance]

2

) 

No conversion is required for the geometric standard deviation and the geometric standard deviation of 

0.23 was used. CMAD is the count median aerodynamic diameter (0.9 μm). 

The NOAEL[HEC] of 0.37 mg/m3

 was divided by an uncertainty factor of 30 (3 for extrapolation from 

animals to humans using dosimetric adjustment and 10 for human variability), resulting in an 

intermediate-duration inhalation MRL of 0.01 mg/m3. Application of the benchmark dose methodology 

to the data from Kimmerle (1976) was considered, but the data were presented as means without standard 
GUTHION A-11 

APPENDIX A 

errors or standard deviations. Without these measures, the benchmark dose methodology could not be 

applied. 

Was a conversion used from intermittent to continuous exposure? Yes, animals were exposed 

6 hours/day, 5 days/week. 

NOAEL[ADJ] = 1.24 mg/m3

 x 6 hours/24 hours x 5 days/7 days 

NOAEL[ADJ] = 0.22 mg/m3 

Other additional studies or pertinent information that lend support to this MRL: No studies were located 

that allowed the derivation of a chronic-duration inhalation MRL. However, the available acute- and 

intermediate-duration inhalation studies and the acute-, intermediate-, and chronic-duration oral exposure 

studies support adopting the intermediate-duration MRL for chronic-duration exposures. Erythrocyte 

AChE activity was reduced by 29–48% in male rats and 26–39% in female rats exposed to guthion 

aerosols at 4.72 mg/m3

 for 4–12 weeks without evident biologically significant changes in activity within 

the observation period (Kimmerle 1976). Intermediate- and chronic-duration oral exposures to 0.69– 

0.78 mg/kg/day in dogs (Allen et al. 1990) and 0.75–0.96 mg/kg/day in rats (Schmidt and Chevalier 

1984) demonstrated biologically significant reductions in erythrocyte AChE activity that did not increase 

in severity with increasing exposure duration for up to 2 years (Allen et al. 1990; Schmidt and Chevalier 

1984). Thus, a chronic-duration inhalation MRL of 0.01 mg/m3

 is adopted from the intermediate-duration 

inhalation MRL and supported by the intermediate- and chronic-duration oral exposure studies in dogs 

and rats, which suggest that there are no duration-dependent increases in the severity of the inhibition of 

erythrocyte AChE activity. 

Agency Contacts (Chemical Managers): Nickolette Roney, Selene Chou, Yee-Wan Stevens 
GUTHION A-12 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Guthion 

CAS Numbers: 86-50-0 

Date: June 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 11 

Species: Rats 

Minimal Risk Level: 0.01 [X] mg/kg/day [ ] ppm 

Reference: Astroff AB, Young AD. 1998. The relationship between maternal and fetal effects following 

maternal organophosphate exposure during gestation in the rat. Toxicol Ind Health 14(6):869-889. 

Experimental design: Pregnant Sprague-Dawley rats were administered guthion (87.7% a.i.) at 0.5, 1.0, 

or 2.0 mg/kg/day by gavage on gestation days 6–15 (Astroff and Young 1998). Erythrocyte AChE was 

determined on gestation days 16 and 20 and brain AChE activity was determined on day 20. Inseminated 

females were examined daily for clinical signs. Dam body weight was determined on gestation days 0, 6, 

8, 10, 12, 15, and 20. Food consumption was also determined periodically. Two groups of dams were 

used to establish maternal plasma ChE and erythrocyte and brain AChE activities on gestation days 

16 and 20. Gross pathological examination of dams was conducted. Several reproductive and 

developmental end points, including early or late resorptions, implantation losses, and fetal survival, 

growth, and malformations were evaluated. 

Effect noted in study and corresponding doses: A >80% reduction in erythrocyte AChE activity was 

observed 24 hours after the last 2.0 mg/kg/day dose. A 40% reduction in brain AChE activity was also 

observed in dams in the 2.0 mg/kg/day group. Maternal plasma ChE activity in the 2.0 mg/kg/day group 

was approximately 30% lower than in controls on gestation day 16, but the effect was not statistically 

significant. On gestation day 20, maternal brain AChE activity remained 27% lower than control values, 

but erythrocyte AChE and plasma ChE activities were not significantly different from those of control 

animals. In spite of the magnitude of the AChE and ChE activity reductions, there were no adverse 

clinical signs observed in the treated dams. There were no statistically or biologically significant 

reductions in brain or erythrocyte AChE or plasma ChE activities in rats administered 0.5 or 1 mg/kg/day. 

Dose and end point used for MRL derivation: The MRL is based on a BMDL of 1.04 mg/kg/day for 

inhibition of erythrocyte AChE activity. 

[ ] NOAEL [ ] LOAEL [X] BMDL 

In order to derive a point of departure to calculate an acute-duration oral MRL, a benchmark dose 

approach was applied to the changes in erythrocyte AChE activity observed in female rats exposed to 

guthion by gavage during gestation. Benchmark doses (BMDs) and the lower bound of the 95% 

confidence limits of the benchmark doses (BMDLs) were calculated using the EPA Benchmark Dose 

Software (BMDS version 1.3.2) as described below. The BMDs and BMDLs are estimates of the doses 

associated with a 20% change in erythrocyte AChE activity. 

The simplest continuous variable model (a linear model) did not provide an adequate fit to the erythrocyte 

AChE activity data. Thus, four continuous variable models were fit to the erythrocyte AChE activity data 

presented in Table A-4. Results of the modeling are presented in Table A-5. 
GUTHION A-13 

APPENDIX A 

Table A-4. Erythrocyte Cholinesterase Activity in Female Rats Administered 

Guthion 

Guthion dose Number of Erythrocyte AChE activity Standard Percent 

(mg/kg/day) animals tested (IU/mL) deviation inhibition 

0 24 0.36 0.10 – 

0.5 19 0.32 0.06 11 

1.0 27 0.32 0.09 11 

2.0 26 0.07 0.03 81 

Source: Astroff and Young 1998 

Table A-5. Model Predictions for Changes in Erythrocyte Cholinesterase Activity 

in Female Rats 

Variance X2

 test statistic p-Value for BMD BMDL 

Model p-valuea for means df the meansa AIC (mg/kg/day) (mg/kg/day) 

Linear

b

 <0.0001 29.9864 2 <0.0001 -369.520477 – – 

Linear

c

 0.1257 34.808 2 <0.0001 -390.935378 – – 

2-degree 0.1257 5.50139 1 0.019 -418.242024 – – 

polynomiald 

Powerc,e 0.1257 3.42361 1 0.06427 -420.319802 1.32753 1.03839 

Hillf

 0.1257 3.42499 0 NA -418.318425 – – 

a

Values <0.05 fail to meet conventional goodness-of-fit criteria. b

Constant variance assumed c

Best-fitting model d

The lowest degree polynomial providing an adequate fit is reported e

Restrict power >=1 f

Restrict n>1 

AIC = Akaike’s Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the benchmark 

dose; df = degree of freedom; NA = not available (BMD software could not generate a model output); p = p-value from 

the chi-squared test 

An adequate fit to the data for changes in erythrocyte AChE activity (as assessed by chi-square residuals 

and log-likelihood ratio fit tests in the BMDS) was obtained only with the power model with nonconstant 

variance assumed. A limitation of this data set is the large difference in maternal erythrocyte AChE 

activity between the NOAEL and the next, higher dose; relative to controls, maternal erythrocyte AChE 

activity was 11% lower in the 1 mg/kg/day group and 81% lower in the 2 mg/kg/day group. Statistical 

tests indicated that variances were not constant across exposure groups. The power model with nonhomogeneous variance (i.e., variance as a power function of dose) provided an improved fit to the data as 

assessed with Akaike’s Information Criteria (AIC) (Table A-5). The BMD and BMDL predicted from the 

power model are 1.33 and 1.04 mg/kg/day, respectively (Table A-5 and Figure A-1). 
GUTHION A-14 

APPENDIX A 

Figure A-1. Model Predictions for Changes in Erythrocyte Cholinesterase Activity 

in Female Rats 

Power Model with 0.95 Confidence Level 

0.05 

0.1 

0.15 

0.2 

0.25 

0.3 

0.35 

0.4 

Mean Response 

BMDL BMD 

Power 

0 0.5 1 1.5 2 

dose 

14:23 04/04 2006 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: Pasquet et al. (1976) 

observed reductions in erythrocyte and brain AChE activity in rats after single oral doses of guthion at 2, 

6, or 18 mg/kg. Plasma ChE activity was reduced by ≥20% at >2 mg/kg, while brain AChE activity was 

reduced by ≥20% at doses ≥2 mg/kg/day. The results of the BMD approach is supported by the 

observation that application of a NOAEL approach (NOAEL ÷ 100 [uncertainty factor] would result in an 

MRL equal to the BMDL ÷ 100 [uncertainty factor]. 

Agency Contacts (Chemical Managers): Nickolette Roney, Selene Chou, Yee-Wan Stevens 
GUTHION A-15 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Guthion 

CAS Numbers: 86-50-0 

Date: June 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 40 

Species: Dog 

Minimal Risk Level: 0.003 [X] mg/kg/day [ ] ppm 

Reference: Allen TR, Janiak T, Frei T, et al. 1990. 52-Week oral toxicity (feeding) study with azinphosmethyl (E 1582) in the dog. Mobay Corporation. Submitted to the U.S. Environmental Protection 

Agency. MRID41804801. 

Experimental design: Technical-grade guthion (91.9% a.i.) was administered to beagle dogs (four 

dogs/sex/group) in the food at 5.0, 25.0, and 125.0 ppm for up to 52 weeks. The guthion concentrations 

are equivalent to 0.15, 0.69, and 3.8 mg/kg/day, respectively, in male dogs, and 0.16, 0.78, and 

4.3 mg/kg/day, respectively, in female dogs (Allen et al. 1990). The observations made at ≤26 weeks 

were used to derive the intermediate-duration MRL. Daily observations for clinical signs were 

conducted; body weight was determined weekly and food consumption was monitored daily. Hearing 

and ophthalmoscopic evaluations were conducted after 13, 26, and 52 weeks; hematological, clinical 

chemistry, and urinary chemistry parameters were determined on weeks 4, 13, 26, and 52; plasma ChE 

and erythrocyte AChE activities were determined on weeks 4, 13, and 26. 

Effect noted in study and corresponding doses: Reductions of ≥20% in erythrocyte AChE activity were 

observed after 4, 13, and 26 weeks in male and female dogs administered guthion in food for up to 

52 weeks (Allen et al. 1990). Dose-related reductions in erythrocyte AChE activity were evident at the 

week 4 sampling time. Erythrocyte AChE activity was further reduced from week 4 to week 13 but 

remained relatively constant from week 13 to 26 (Allen et al. 1990). Statistically nonsignificant 

reductions in erythrocyte AChE activity during the 26-week period were ≤8% in males at 0.15 mg/kg/day 

and 11–21% in females at 0.16 mg/kg/day. Reductions in erythrocyte AChE activity were 22–40% in 

males at 0.69 mg/kg/day and 20–43% in females at 0.78 mg/kg/day. Reductions in erythrocyte AChE 

activity from weeks 4 to 26 were 66–88% in males (3.8 mg/kg/day) and 86–92% in females 

(4.3 mg/kg/day). The relatively constant levels of erythrocyte AChE activity from weeks 4 to 26 suggest 

that the effects of guthion on AChE activity occur early and remain relatively steady during exposure. 

Male and female dogs administered 3.8 and 4.3 mg/kg/day, respectively, suffered from an increased 

incidence of mucoid diarrhea and occasional emesis. The same signs but with a greater severity were 

observed in male dogs at 0.69 mg/kg/day. These signs were believed to be related to guthion treatment. 

Terminal body weights were reduced by 12–16% in male and female dogs administered 3.8 and 

4.3 mg/kg/day, respectively, although there was no difference in food consumption among treated and 

control animals. There were no treatment-related hematological effects or changes in urinalysis 

parameters. Findings were negative in hearing and ophthalmoscopic tests on weeks 13 and 26 and there 

was no treatment-related increase in mortality in any dose group (Allen et al. 1990). Clinical chemistry 

tests showed that albumin and albumin/globulin values were significantly reduced in males by 13 and 

20%, respectively, in the 3.8 mg/kg/day group. 
GUTHION A-16 

APPENDIX A 

Dose and end point used for MRL derivation: The MRL is based on a BMDL of 0.29 mg/kg/day for 

inhibition of erythrocyte AChE activity in female dogs after 26 weeks. 

[ ] NOAEL [ ] LOAEL [X] BMDL 

In order to derive a point of departure to calculate an intermediate-duration oral MRL, a benchmark dose 

approach was applied to the changes in erythrocyte AChE activity observed in male and female dogs 

exposed to guthion in the diet for 26 weeks (Allen et al. 1990). It is recognized that the small number of 

animals per dose group (4 dogs/group) limits the characterization of variability in the response to guthion. 

Benchmark doses (BMDs) and the lower bound of the 95% confidence limits of the benchmark doses 

(BMDLs) were calculated using the EPA Benchmark Dose Software (BMDS version 1.3.2) as described 

below. The BMDs and BMDLs are estimates of the doses associated with a 20% change in erythrocyte 

AChE activity. The simplest continuous variable model (a linear model) was fit to the erythrocyte AChE 

activity data presented in Table A-6. 

Table A-6. Erythrocyte Cholinesterase Activity (μmol/mL/minute) in Beagle 

Dogs Administered Guthion in the Diet for 

26 Weeks (Four Dogs/Sex/Dose Group) 

Dose (mg/kg/day) Mean (standard deviation) Percent reduction 

Males 

0 2.57 (0.29) – 

0.15 2.37 (0.83) 8 

0.69 1.75 (0.21) 32 

3.8 0.32 (0.13) 88a

Females 

0 3.27 (0.38) – 

0.16 2.57 (0.63) 21 

0.78 2.03 (0.53) 37a 

4.3 0.28 (0.11) 91a 

a

Statistically significant reduction 

Source: Allen et al. 1990 

A nonhomogeneous variance linear model provided an adequate fit to the erythrocyte AChE activity data 

for female but not male dogs after 26–week and it was concluded that the male data at 26 weeks were not 

suitable for BMD modeling. For the 26-week data in female dogs, the best-fitting linear model predicted 

a BMD of 0.96 mg/kg/day and a BMDL of 0.93 mg/kg/day. However, this BMDL for a 20% reduction in 

erythrocyte AChE activity in dogs is higher than the observed LOAELs of 0.69 and 0.78 mg/kg/day in 

male and female dogs, respectively (Allen et al. 1990). At these LOAELs, reductions in erythrocyte 

AChE activity in the range of 32–37% were observed after 26 weeks. Thus, the linear model appears to 

underpredict the response of erythrocyte AChE activity to guthion in female dogs after 26 weeks. 

Reexamination of the data plots suggests that the experimental data at the high dose might be a highleverage point, which exerts a high degree of influence on the model results. The plot of the erythrocyte 

AChE activity in female dogs after 26 weeks is presented in Figure A-2. Given that for the derivation of 

an MRL the most pertinent part of the dose-response curve is that which lies at the lower doses, the highdose data point was removed from the dataset and the model fitting was conducted as described before. A 

nonhomogeneous variance linear model provided an adequate fit to the erythrocyte AChE activity data for 

females at week 26 when the high dose was removed from the data set. None of the other continuous 
GUTHION A-17 

APPENDIX A 

models available in the BMD software provided an adequate fit to the data. Results of the BMD linear 

modeling of the low-dose region of the dose-response curve are presented in Table A-7 and a plot of the 

26-week data in females with the high-dose excluded is presented in Figure A-3. 

Table A-7. Model Predictions for Erythrocyte AChE Activity in Female Beagle 

Dogs Exposed to Guthion in the Diet for 26 Weeks 

X2

 test 

Variance p- statistic p-value for BMD BMDL 

Model valuea for means df the meansa AIC (mg/kg/day) (mg/kg/day) 

Linear

b,c,d 0.43 2.47 1 0.12 3.12 0.44 0.29 

(high dose 

excluded) 

a

Values <0.05 fail to meet conventional goodness-of-fit criteria. b

Constant variance assumed c

Best-fitting model d

Restriction = nonpositive 

AIC = Akaike’s Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the 

benchmark dose; df = degree of freedom; p = p value from the Chi-squared test 
GUTHION A-18 

APPENDIX A 

Figure A-2. Erythrocyte AChE Activity in Female Beagle Dogs Exposed to 

Guthion in the Diet for 26 Weeks*(Complete Dataset) 

Linear Model with 0.95 Confidence Level 

0 

0.5 

1 

1.5 

2 

2.5 

3 

3.5 

4 

Mean Response 

BMDL BMD 

Linear 

0 1 2 3 4 

dose 

14:14 04/20 2006 

*BMDs and BMDLs are associated with a 20% change from the controls, and are in units of mg/kg/day. 
GUTHION A-19 

Mean Response 

APPENDIX A 

Figure A-3. Erythrocyte AChE Activity in Female Beagle Dogs 

Exposed to Guthion in the Diet for 26 Weeks* 

(High-dose Group Excluded) 

Linear Model with 0.95 Confidence Level 

4 

3.5 

3 

2.5 

2 

1.5 

1 

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 

BMDL BMD 

Linear 

dose 

08:55 06/12 2006 

*BMDs and BMDLs indicated are associated with a change of 20% change from the control, and are in units of 

mg/kg/day 
GUTHION A-20 

APPENDIX A 

A BMDL of 0.29 mg/kg/day was obtained by analysis of the low-dose region of the dose-response curve 

for dogs exposed for 26 weeks. 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: Inhibition of erythrocyte 

AChE activity was the most sensitive end point in a study with male and female rats administered 

technical-grade guthion in the feed for 13 weeks (Sheets et al. 1997). Brain and erythrocyte AChE 

activities were significantly inhibited in rats administered ≥0.91 mg/kg/day. The results obtained using 

the BMD approach are supported by those obtained using the NOAEL approach. 

Agency Contacts (Chemical Managers): Nickolette Roney, Selene Chou, Yee-Wan Stevens 
GUTHION A-21 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Guthion 

CAS Numbers: 86-50-0 

Date: June 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 63 

Species: Dog 

Minimal Risk Level: 0.003 [X] mg/kg/day [ ] ppm 

Reference: Allen TR, Janiak T, Frei T, et al. 1990. 52-Week oral toxicity (feeding) study with azinphosmethyl (E 1582) in the dog. Mobay Corporation. Submitted to the U.S. Environmental Protection 

Agency. MRID41804801. 

Experimental design: Technical-grade guthion (91.9% a.i.) was administered to beagle dogs (four 

dogs/sex/group) in the food at 5.0, 25.0, 125.0 ppm for up to 52 weeks. The guthion concentrations are 

equivalent to 0.15, 0.69, and 3.8 mg/kg/day, respectively, in male dogs, and 0.16, 0.78, and 

4.3 mg/kg/day, respectively, in female dogs (Allen et al. 1990). Daily observations for clinical signs were 

conducted; body weight was determined weekly and food consumption was monitored daily. Hearing 

and ophthalmoscopic evaluations were conducted after 13, 26, and 52 weeks; hematological, clinical 

chemistry, and urinary chemistry parameters were determined on weeks 4, 13, 26, and 52; plasma ChE 

and erythrocyte AChE activities were determined prior to treatment and on weeks 4, 13, 26, and 52; brain 

AChE activity was determined on week 52. Terminal body weight and organ weights were determined 

and macroscopic and histopathological evaluations of organs were conducted. 

Effect noted in study and corresponding doses: Dose-related reductions in erythrocyte AChE activity 

were evident in male and female dogs on week 52. A statistically nonsignificant reduction of 15% in 

erythrocyte AChE activity was observed in females at 0.16 mg/kg/day on week 52, but there was no 

effect in males. On week 52, reductions in erythrocyte AChE activity in males at 0.69 and 3.8 mg/kg/day 

were 27 and 86%, respectively. Females in the 0.78 and 4.3 mg/kg/day groups showed 35 and 86% 

reductions, respectively, in erythrocyte AChE activity. Brain AChE activity on week 52 in the 3.8 and 

4.3 mg/kg/day groups was reduced by 27 and 20% in males and females, respectively. Reductions in 

brain AChE activity were 1 and 10% in female and male dogs receiving administered 0.78 and 

0.69 mg/kg/day, respectively. No effect on brain AChE activity was observed in males administered 

0.15 mg/kg/day or females administered 0.16 mg/kg/day. Plasma ChE activity was reduced by 53% in 

males and females administered 3.8 and 4.3 mg/kg/day, respectively. No statistically significant 

reductions in plasma ChE activity were observed in male or female dogs administered ≤0.69 or 

≤0.78 mg/kg/day, respectively. Terminal body weights were reduced by 12% in males in the 

3.8 mg/kg/day group and by 16% in females in the 4.3 mg/kg/day group, although there was no difference 

in food consumption among treated and control animals. There were no treatment-related hematological 

effects or changes in urinalysis parameters. Findings were negative in hearing and ophthalmoscopic tests 

conducted at study termination and there was no treatment-related increase in mortality in any dose group. 

There were no changes in absolute or relative organ weights in females at the doses tested. Absolute and 

relative spleen weights in were reduced in males in a dose-related manner with significant reductions in 

relative spleen weight at ≥0.69 mg/kg/day; however, congestion of the spleen and increased absolute 

spleen weight were observed in 4/4 male dogs in the control group. A 7–17% decrease in albumin and 

albumin/globulin values were observed on week 52 in males in the 3.8 mg/kg/day group. A 39 and 15% 

increase in P450 activity was observed in male dogs at 3.8 mg/kg/day and in female dogs at 
GUTHION A-22 

APPENDIX A 

4.3 mg/kg/day, respectively. A 34 and 30% increase in N-demethylase activity was observed in male 

dogs at 3.8 and in female dogs at 4.3 mg/kg/day, respectively. Other effects were restricted to the high 

dose groups (Allen et al. 1990). 

Dose and end point used for MRL derivation: The MRL is based on a BMDL of 0.30 mg/kg/day for 

inhibition of erythrocyte AChE activity in male dogs after 52 weeks. 

[ ] NOAEL [ ] LOAEL [X] BMDL 

In order to derive a point of departure to calculate a chronic-duration oral MRL a benchmark dose 

approach was applied to the changes in erythrocyte AChE activity observed in male and female dogs 

exposed to guthion in the diet for 52 weeks (Allen et al. 1990). It is recognized that the small number of 

animals per dose group (4 dogs/group) limits the characterization of variability in the response to guthion. 

Benchmark doses (BMDs) and the lower bound of the 95% confidence limits of the benchmark doses 

(BMDLs) were calculated using the EPA Benchmark Dose Software (BMDS version 1.3.2) as described 

below. The BMDs and BMDLs are estimates of the doses associated with a 20% change in erythrocyte 

AChE activity. The simplest continuous variable model (a linear model) was fit to the erythrocyte AChE 

activity data presented in Table A-8. 

Table A-8. Erythrocyte Cholinesterase Activity (μmol/mL/minute) in Beagle 

Dogs Administered Guthion in the Diet for 52 Weeks 

(Four Dogs/Sex/Dose Group) 

Dose (mg/kg/day) Mean (standard deviation) Percent reduction 

Males 

0 2.87 (0.36) – 

0.15 3.01 (0.84) 0 

0.69 2.10 (0.45) 27 

3.8 0.41 (0.15) 86a 

Females 

0 3.36 (1.72) – 

0.16 2.87 (0.73) 15 

0.78 2.20 (0.5) 35a 

4.3 0.47 (0.16) 86a 

a

Statistically significant reduction 

Source: Allen et al. 1990 

The linear model under the assumption of constant variance did not provide an adequate fit for either the 

male or female erythrocyte AChE activity data at 52 weeks; however, a nonhomogeneous variance linear 

model provided an adequate fit to the erythrocyte AChE activity data for males and females at week 52. 

Therefore, the linear model with the assumption of nonhomogenous variance was chosen for estimating 

the BMDs and BMDLs for the males and females at week 52. The selected model predicted a BMD in 

the range of 0.90–1.0 mg/kg/day and a BMDL in the range of 0.85–0.97 mg/kg/day. However, these 

BMDLs for a 20% reduction in erythrocyte AChE activity in dogs are higher than the observed LOAELs 

of 0.69 and 0.78 mg/kg/day in male and female dogs, respectively (Allen et al. 1990). At these LOAELs, 

reductions in erythrocyte AChE activity in the range of 27–35% were observed after 52 weeks. Thus, the 

linear model appears to underpredict the response of erythrocyte AChE activity to guthion in dogs after 
GUTHION A-23 

APPENDIX A 

52 weeks. Reexamination of the data plots suggests that the experimental data at the high dose might be a 

high-leverage point which exerts a high degree of influence on the model results. The plots of the 

erythrocyte AChE activity in male and female dogs after 52 weeks are presented in Figures A-4(A) and 

A-5(A), respectively. Given that for the derivation of an MRL the most pertinent part of the doseresponse curve is that which lies at the lower doses the high-dose data point was removed from the dataset 

and the model fitting was conducted as described before. A linear model with an assumption of 

homogenous variance provided an adequate fit to the 52-week data with dogs when the high-dose data 

were removed. The other continuous models in the software were also applied to the data, but did not 

provide adequate fits. Results of the BMD linear modeling of the low-dose region of the dose-response 

curve are presented in Table A-9. Plots of the 52-week data in males and females with the high-dose 

excluded are presented in Figures A-4(B) and A-5(B), respectively. 

Table A-9. Model Predictions for Erythrocyte AChE Activity in Beagle Dogs 

Exposed to Guthion in the Diet for 52 Weeks 

X2

 test 

Variance statistic for p-value for the BMD BMDL 

Model p-valuea means df meansa AIC (mg/kg/day) (mg/kg/day) 

Male 

Linear

b,c 0.20 0.85 1 0.36 0.66 0.48 0.30 

(high dose 

dropped) 

Female 

Linear

b,c 0.55 1.5 1 0.23 14.5 0.50 0.32 

(high dose 

dropped) 

a

Values <0.05 fail to meet conventional goodness-of-fit criteria. b

Constant variance assumed c

Restriction = nonpositive 

AIC = Akaike’s Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the 

benchmark dose; df = degree of freedom; p = p value from the Chi-squared test 
GUTHION A-24 

APPENDIX A 

Figure A-4. Erythrocyte AChE Activity in Male Beagle Dogs Exposed to Guthion 

in the Diet for 52 Weeks* 

Linear Model with 0.95 Confidence Level 

0 

1 

2 

3 

4 

All dose groups included 

BMDL BMD

Linear 

Mean Response 

0 

12:37 04/20 2006 

0.5 1 1.5 2 

dose 

2.5 3 3.5 4 

Linear Model with 0.95 Confidence Level 

1.5 

2 

2.5 

3 

3.5 

4 

4.5 

Mean Response 

BMDL BMD

Linear 

High dose group excluded 

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 

dose 

11:34 06/12 2006 

*BMDs and BMDLs are associated with a 20% change from the controls, and are in units of mg/kg/day. 
GUTHION A-25 

APPENDIX A 

Figure A-5. Erythrocyte AChE Activity in Female Beagle Dogs 

Exposed to Guthion in the Diet for 52 Weeks* 

Linear Model with 0.95 Confidence Level 

0 

1 

2 

3 

4 

5 

6 

BMDL BMD

Linear 

Mean Response 

All dose groups included 

0 1 2 3 4 

dose 

12:42 04/20 2006 

Linear Model with 0.95 Confidence Level 

1 

2 

3 

4 

5 

6 

Mean Response 

BMDL BMD 

Linear 

High dose group excluded 

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 

dose 

13:23 06/16 2006 

*BMDs and BMDLs are associated with a 20% change from controls, and are in units of mg/kg/day. 
GUTHION A-26 

APPENDIX A 

BMDLs of in the range of 0.30–0.32 mg/kg/day were obtained by analysis of the low-dose region only of 

the dose-response curve for dogs exposed for 52 weeks. The lowest BMDL (0.30 mg/kg/day) was 

selected as the point of departure. Applying an uncertainty factor of 100 (10 for extrapolation from 

animals to humans and 10 for human variability) to the BMDL yields a chronic-duration oral MRL of 

0.003 mg/kg/day. 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: Inhibition of erythrocyte 

AChE activity also was the most sensitive effect in a 2-year study with rats administered guthion in the 

diet at 0.25–2.3 mg/kg/day in males and 0.31–3.11 mg/kg/day in females (Schmidt and Chevalier 1984). 

These studies support selection of the effect on erythrocyte AChE activity as the critical end point for 

chronic oral exposure to azinphos-methyl. The 52-week study in dogs (Allen et al. 1990) was selected to 

derive the chronic-duration oral MRL because, at similar doses (0.69–0.78 mg/kg/day in dogs after 

52 weeks and 0.75–0.96 mg/kg/day in rats after 2 years), there was a more marked reduction in 

erythrocyte AChE in dogs (20–43%) than in rats (10–22%). 

Agency Contacts (Chemical Managers): Nickolette Roney, Selene Chou, Yee-Wan Stevens 
GUTHION B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1. What effects are known to occur in humans? 

2. What effects observed in animals are likely to be of concern to humans? 

3. What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 
GUTHION B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
GUTHION B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1) Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2) Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3) Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4) Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5) Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6) Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7) System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 
GUTHION B-4 

APPENDIX B 

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10) Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11) CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13) Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14) Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15) Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in 

mg/kg/day. 

(16) NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17) CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
GUTHION B-5 

APPENDIX B 

(18) Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19) Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
SAMPLE 

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

Key to figurea 

Exposure frequency/ 

Species duration System 

NOAEL (ppm) 

LOAEL (effect) 

Less serious (ppm) 

Serious (ppm) 

Re

2 → INTERMEDIATE EXPOSURE 3 4 

5 6 7 8 9 10

→ Systemic ↓ ↓ ↓ ↓ ↓ ↓→

13 wk 5 d/wk 6 hr/d 

18 RatCHRONIC EXPOSURE 

Resp 3b 10 (hyperplasia) 

Nit

Cancer 

↓

38 39 40 

Rat Rat Mouse 

18 mo 5 d/wk 7 hr/d 89–104 wk 5 d/wk 6 hr/d 79–103 wk 5 d/wk 6 hr/d 

20 10 10 

(CEL, multiple organs) (CEL, lung tumors, nasal tumors) (CEL, lung tumors, hemangiosarcomas) 

WNTNT

11 

12 → a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

GUTHION B-8 

APPENDIX B 

This page is intentionally blank. 
GUTHION C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD benchmark dose 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/Intergovernmental Maritime Dangerous Goods Code 
GUTHION C-2 

APPENDIX C 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 
GUTHION C-3 

APPENDIX C 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 
GUTHION C-4 

APPENDIX C 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
GUTHION C-5 

APPENDIX C 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta μm micrometer μg microgram

* 

q1 cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
GUTHION C-6 

APPENDIX C 

This page is intentionally blank. 
GUTHION D-1 

APPENDIX D. INDEX 

absorbed dose..............................................................................................................................................83 

acetylcholine ....................................................................................... 11, 26, 32, 54, 78, 82, 86, 91, 98, 152 

acetylcholinesterase .......................................................... 5, 10, 26, 77, 82, 86, 88, 131, 136, 146, 152, 158 

adipose tissue ............................................................................................................................................129 

adrenals ........................................................................................................................................... 16, 27, 51 

adsorption.................................................................................................................................. 114, 115, 142 

aerobic................................................................................................................................... 9, 109, 118, 120 

ambient air ................................................................................................................................................128 

anaerobic...................................................................................................................................................121 

atropine ........................................................................................................................................... 85, 88, 98 

bioaccumulation................................................................................................................................ 116, 142 

bioavailability ...........................................................................................................................................142 

bioconcentration factor .............................................................................................................................116 

biodegradation................................................................................................................... 117, 118, 120, 142 

biomarker .................................................................................................................. 82, 83, 84, 96, 145, 149

body weight effects ......................................................................................................................... 27, 52, 61 

breast milk......................................................................................................................................... 131, 143 

cancer .............................................................................................................................. 3, 33, 57, 64, 81, 93 

carcinogen.................................................................................................................................................158 

carcinogenic ........................................................................................................................ 12, 13, 25, 58, 93 

carcinogenicity.................................................................................................................... 12, 57, 58, 91, 93 

carcinoma........................................................................................................................................ 12, 57, 93 

cardiovascular ........................................................................................................................... 34, 61, 63, 78 

cardiovascular effects..................................................................................................................................34 

cholinesterase........................................................................ 4, 11, 32, 54, 56, 57, 72, 84, 86, 145, 146, 152 

death................................................................................................................................ 3, 12, 25, 27, 34, 57 

deoxyribonucleic acid (see DNA)...............................................................................................................67 

DNA (see deoxyribonucleic acid)......................................................................................................... 67, 83 

endocrine............................................................................................................................. 11, 61, 78, 79, 80 

endocrine effects .........................................................................................................................................51 

fetus.............................................................................................................................................................80 

gastrointestinal effects ................................................................................................................................34 

general population................................................................... 10, 82, 91, 109, 111, 128, 137, 138, 139, 143 

genotoxic......................................................................................................................................... 25, 64, 94 

genotoxicity........................................................................................................................................... 64, 94 

groundwater .............................................................................................. 2, 9, 109, 113, 114, 124, 125, 148

half-life............................................................................................ 73, 83, 96, 109, 117, 118, 120, 143, 145 

hematological effects ................................................................................................................ 21, 23, 34, 61 

hepatic effects .............................................................................................................................................51 

hydrolysis............................................................................ 72, 108, 109, 117, 118, 120, 141, 142, 146, 148 

hydroxyl radical ................................................................................................................................ 109, 117 

immunological .............................................................................................................. 11, 25, 27, 32, 53, 78

Kow .................................................................................................................................................... 103, 116 

LD50..................................................................................................................................... 33, 34, 58, 63, 92 

lymphoreticular............................................................................................................................... 27, 32, 53 

metabolic effects................................................................................................................................... 34, 61 

micronuclei .................................................................................................................................................64 

milk ................................................................................................................................................... 148, 151 

muscarinic receptor............................................................................................................................... 78, 88 
GUTHION D-2 

APPENDIX D 

musculoskeletal effects...............................................................................................................................51 

neonatal.....................................................................................................................................................131 

neoplastic ....................................................................................................................................................57 

neurobehavioral...........................................................................................................................................80 

neurotransmitter ........................................................................................................................ 11, 78, 91, 98 

nicotinic receptor .................................................................................................................................. 32, 78 

ocular effects...............................................................................................................................................52 

odds ratio.....................................................................................................................................................64 

pharmacodynamic .......................................................................................................................................74 

pharmacokinetic.................................................................................................................. 74, 75, 76, 80, 98 

photolysis .......................................................................................................... 109, 117, 118, 120, 121, 142

placenta ............................................................................................................................................. 131, 136 

rate constant ..............................................................................................................................................117 

renal effects........................................................................................................................................... 51, 61 

salivation................................................................................................................. 11, 18, 20, 52, 54, 63, 78 

serum glutamic oxaloacetic transaminase...................................................................................................16 

serum glutamic pyruvic transaminase.........................................................................................................16 

solubility ...................................................................................................................................................113 

thyroid..................................................................................................................... 13, 16, 27, 51, 57, 58, 93 

toxicokinetic........................................................................................................................ 25, 77, 79, 98, 99 

tremors ............................................................................................................................................ 20, 52, 56 

tumors ............................................................................................................................................. 13, 57, 93 

vapor pressure ................................................................................................................................... 113, 117 

volatility ......................................................................................................................................................26 

volatilization .............................................................................................................................................113