JON E. FORD, Ph.D.

Chevron Environmental Health Center

Recently, concern has been expressed that the normal agricultural use of Paraquat may cause adverse lung effects. Perhaps this concern could be alleviated by discussing some facts regarding Paraquat.

Figure 1 presents the molecular structure of the Paraquat cation. It is composed of two pyridine rings with a methyl group attached to each of the rings. Paraquat is formulated as the dichloride salt; however, the cation is the active herbicidal and toxic agent. Paraquat is a flat molecule and becomes inactivated when in contact with clay particles. The molecule apparently fits into the clay lattice and forms an irreversible bond. It is this unique binding property with clay that serves as the basis for the recommended treatment regimen for Paraquat poisoning.

The vapor pressure of Paraquat is negligible: therefore, no adverse health effects are expected following exposure to Paraquat vapor. The solvent in Paraquat consists of water with a trace of methanol.

Agriculturally. Paraquat is used widely as a general contact herbicide, cotton harvest aid, a desiccant for sugarcane, sunflowers, and soy beans, and has utility as a pre-emergent herbicide for such crops as asparagus, cotton, corn. lettuce and wheat.

Paraquat is manufactured by Imperial Chemical Industries, Ltd. (ICD) in Great Britain and marketed throughout the world. Chevron Chemical Company is the distributor of Paraquat in the United States.

The main agricultural Paraquat formulation sold in this country is ORTHO Paraquat CL. As indicated in Table 1. this product contains 21.07% Paraquat cation. The ORTHO Dual Paraquat consists of the methyl sulfate salt, and is no longer marketed. ORTHO Spot Weed and Grass Killer is the garden and home formulation and contains 0.2% of the Paraquat cation. As mentioned above, the agricultural Paraquat for

mulation consists basically of 21% Paraquat cation in water. Thus, each milliliter of Paraquat concentrate contains approximately 240 mg cation.

Chevron Chemical Company is only a distri butor of Paraquat, nevertheless, the company maintains an active toxicology program in conducting laboratory investigations and providing Treatment of Paraquat poisoning. I am one of several toxicologists employed at the Chevron Environmental Health Center (CEHC) in Rich mond California. Aside from conducting toxicol ogy studies and dealing with other matters concerning product evaluation, the CEMC also has a Poison Information Center for all of the Chevron Chemical Company pesticide products. The emergency telephone number (415) 233-3737, of the Chevron Poison Information Center (CPIC), appears on all product labels. This is a 24-hour service to physicians, veterinarians, other members of the medical profession as well as cus tomers, concerning the toxicology of Chevron Ortho pesticide products. This service was ini tiated in 1974 and since that time approximately 5000 calls are received annually. This has enabled us to gain considerable knowledge concerning the way the products are used and the adverse health effects overexposed persons have experienced.

The most serious calls that we receive concern the swallowing of Paraquat. Since both the toxicology of the chemical and the recommended medical treatment is specific, the toxicologist

TABLE I

spends a great deal of time consulting with the attending physicians and evaluating the findings from Paraquat analyses of the urine, blood and dialysate.

Unlike many other agricultural chemicals, overexposure to properly diluted Paraquat spray mist is not expected to result in systemic toxicity. Paraquat is an irritating chemical, thus overexposure results typically in signs and symptoms of upper respiratory tract or skin irritation. This finding is based on several hundred telephone calls the CPIC has received regarding this subject in addition to ICI's data and the medical literature confirming that overexposure during agricultural use of Paraquat does not result in poisoning. Although Paraquat has been detected in the blood and urine of some workers who have either received extensive skin contact with the concen trate or daily inhalation exposure to the spray mist, it is only in unustral situations that these patients develop signs or symptoms of systemic involvement. Once the exposure is discontinued. the signs and symptoms of imitation disappear within a few days.

The medical literature reports several cases of systemic Paraquat poisoning and death resulting from dermal contact with the chemical How ever, a review of these cases reveals that the subjects either had pre existing dermal lesions prior to the spraying of l'araquat or otherwise practiced poor personal hygiene, thus allowing the chemical to remain in contact with their skin. In this manner, Paraquat either entered the blood directly or damaged the dermal barrier due to the prolonged contact, and eventually gained access into the system.

Again, it is important to emphasize that we are not aware of any substantiated case reports as sociating inhalation of Paraquat spray mist with the development of systemic poisoning. It should

be noted that agricultural spray equipment is not designed to generate respirable spray particles; therefore, the majority of the inhaled droplets are too large (particle mean diameter 200 μ) to reach the alveolar spaces and are deposited in the mucosa of the upper respiratory tract. Thus, in cases of overexposure to l'araquat spray mist, the particles that impinge on the mucosa of the upper respiratory tract produce localized irritation and become manifest by the development of signs and symptoms of nosebleed, sore throat and coughing, Table II.

Systemic Paraquat poisoning, as the result of either ingestion of the chemical or entry through a dermal lesion. follows a characteristic clinical course, Table III. Ingestion of the chemical involves an initial gastrointestinal phase as evidenced by nausea, vomiting and diarrhea. Since the lung is the target organ in Paraquat poisoning, due to the pneumocytes' ability to ac cumulate the chemical from the blood, it is imperative that the recommended treatment be implemented immediately. Other organ systems that may be affected during the first week are the kidneys, liver, and adrenals.

Early diagnosis of systemic Paraquat poisoning can be determined by noting any elevation in BUN and creatinine levels in addition to analysis of blood and urine for the chemical. Chest x-ray and blood gas analysis also may be helpful in determining the degree of systemic involvement. If

TABLE II

Signs and Symptoms of Paraquat Overexposure Inhalation of spray mid

1 Nosebleed

2 Sore throat

A Coughing

1 Head he 3 Nausea

B. Skin concentrate)

1 Severe irritation.

2 Cracking and shedding of nails

$ Skin dilutel

1 Mild irritation

2 White spots on nails

D Ive concentrate

Severe inflanumation

2. Mix involve cormal epithelium Sloss healing:

proper therapeutic efforts are not exercised during the first 24-hours, the patient's chance of a favorable prognosis diminishes. Although not defined fully, it appears that at a certain point, the pneumocytes may accumulate sufficient Paraquat beyond a critical level to render the lung damage irreversible. The pneumocytes then die and are stripped from the alveolar basement membrane. Gas exchange becomes difficult and, due to the increasing accummulation of fluid and cells within the air spaces, inadequate oxygenation results. As in all cases of tissue damage, the body responds by triggering a migration of fibroblasts to the site of injury, thus resulting in the deposition of fibrotic or scar tissue in the lung. Such an event signifies the final pathological event in the Paraquat poisoning. At this stage, in most cases 2-3 weeks after ingestion, gas exchange is minimal and death generally occurs.

As a matter of interest, a treatment for Paraquat poisoning exists and has proven to be effective, Table IV. It consists basically of removing or inactivating Paraquat in the gut and purging the chemical from the blood. The former procedure is accomplished by induction of vomiting, gastric Lavage, whole gut perfusion, and repeated administration of suspensions of clay, eg, Bentonite or Fuller's earth. Utilization of forced diuresis, continuous hemodialysis and/or hemoperfusion during the first few days will lower the Paraquat

blood level significantly. The medical manage ment axiom to be stressed in Paraquat poisoning is to keep the blood concentration of l'araquat as low as possible in order to minimize the avail ability of the chemical to the pneumocytes.

It has been determined that both the rat and man are affected in a similar biochemical and pathological manner by Paraquat." This is evidenced by the rate of accumulation of Paraquat by the pneumocytes and the specific type of lung lesion that subsequently develops. Based on these findings, it appears that the rat serves as a good model to evaluate the toxicology of Paraquat as it applies to man.

Wyatt et al recently conducted Paraquat rat intrabronchial instillation studies, using 10 μg to 1.0 pg quantities of the chemical." The purpose of their study was to determine a no-effect level of Paraquat and the rate of elimination or clearance of Paraquat from the lung once it was deposited in the alveolar spaces.

Using radiolabeled Paraquat, they found that the chemical follows a two-phase elimination. Regardless of the amount instilled, approximately 50% of the Paraquat was eliminated from the fung

during the first hour. Most of the remaining Paraquat was climinated during the second phase which continued for the next 72 hours. They found that during the second phase the higher doses of Paraquat were eliminated the fastest. The investigators state that the reason for this finding may be that the higher Paraquat concentrations are more irritating, thus resulting in edema and cellular damage which may promote a more rapid removal of the chemical into the blood stream.

The investigators determined that when Paraquat was instilled into the lung in doses of 100 ng or less, no histological lung changes were observed. Animals receiving 10 μg demonstrated Jung changes throughout the study while instillation of 1.0 μg resulted in minimal effects after 2 days, however these changes were not evident by 14 days. The authors concluded that a definite no-effect level of instilled Paraquat in the rat lung Can be demonstrated.

In a previous similar investigation, using rabbits, Zavalla demonstrated that pulmonary irritation occurred in the animals administered picogram quantities of Paraquat!" However, it should be noted that the systemic effect of Paraquat in the rabbit differs in comparison to rat or man."

The TIV is based primarily on the findings from the rat Paraquat inhalation studies conducted by Cage. He demonstrated that no pulmonary lesions occurred in rats exposed to Paraquat at a level of 100μg/m' for 6-hours/da/3-weeks. Recent studies by Smith et al” have confirmed Gage's earlier work. These investigators determined that the rat 6-hour 1.C for Paraquat is approximately 1000 μg/m3. They also found that animals exposed to 650 μg Paraquat/m ̈" developed lung fibrosis and some deaths occurred. Smith found that when rats were exposed to 100 μg/m1 of Paraquat some laryngeal irritation but no pulmonary changes were observed. However, laryngeal irritation did not occur in animals exposed to 10μg/m of Paraquat. Table V provides an outline of the findings from these studies.

Smith and coworkers also demonstrated that the animal's lung levels of Paraquat reached a steady state during subchronic Inhalation exposure to the chemical. It was determined that rats exposed to 100 μg Paraquat/m' attained a constant lung concentration of 1.3 μg Paraquat/g wet weight lung after 5 exposures. This lung level of Paraquat remained for the duration of the study. Animals exposed to higher doses of Paraquat reached an early plateau level of the chemical in the lung however, between exposures 5-15, there was evidence of decreasing concentrations indicating the development of lung damage with subsequent clearance of the chemical.

The studies also revealed that the half-life of Paraquat in rat lung, following inhalation exposure to the chemical, was approximately 2 days. This consistency prevailed regardless of whether the animals were exposed once to 500 μg Paraquat 'm'or received 15 exposures to 100 and 500 μg Paraquat/m 1

It appears that the current TLV for respirable Paraquat is supported by both animal inhalation and lung instillation studies. An effect level for the amount of respirable Paraquat required to produce lung fibrosis has been demonstrated adequately by results from several investigations. Further support for the TLV is provided by the absence of any substanstiated cases of pulmonary fibrosis or poisoning following overexposure to Paraquat spray mist during agricultural use of the chemical.

Since the late 1960's, there have been several Paraquat worker exposure studies conducted throughout the world. The first investigation was directed by Swann, who studied a group of Paraquat spray workers in Malaysia," These people, using knapsack sprayers, sprayed Para quat exclusively and took little precaution in avoiding Inhalation and dermal exposure to the Paraquat spray mist. During the 12-week study. physical examinations, chest x-rays, and analysis of urine for Paraquat were conducted on the workers. Although 0.3 to 0.3 ppm was the highest amount of Paraquat detected in some urine samples, none of the spray workers developed any adverse health effects or pulmonary problems.

A more recent study by ICI also was conducted on Malaysian Paraquat spray workers."" Essentially, the worker's practice of disregard for use of protective equipment while working with the chemical had not changed since Swamy's study in 1968. This investigation included a more sophisticated protocol evaluating the sprayer's exposure to respirable and total l'araquat, pulmonary func tion testing, chest x-rays, hematology, blood, and urine chemistry in addition to analysis of blood and urine for Paraquat. The mean total Paraquat concentration, as determined in the breathing zone of these workers, ranged between 0.5 to 3.0 /m', with a mean concentration of approximately 1.0μg/m'. Medical examinations and tests conducted before, during and after the spraying. revealed no adverse health effects.

These studies are further supported by findings from other investigations. Wolfe et al conducted a Paraquat exposure study involving tractor boomrig sprayers, while Hogarty' evaluated the exposure to knapsack Paraquat sprayers. No Paraquat was detected in the breathing zone of the boom-rig sprayers; however, Hogarty found 10 g/m as the greatest breathing zone Paraquat concentration in his test group.

A recent study directed by Chester of ICI, concerned the assessment of Paraquat exposure to workers involved in the acrial application of the chemical on cotton fields in California. The study group consisted of two pilots, two flaggers, and one mixer-loader. Both the amount of respirable and total Paraquat in the breathing zone was determined. The greatest level of Paraquat detected was 26 μg m' total Paraquat, in the

breathing zone of a flagger. No respirable Paraquat was detected in the breathing zone of any of the test subjects.

In conclusion, evidence to date indicates that workers involved in normal agricultural use of Paraquat do not develop residual adverse health effects. Persons overexposed to Paraquat spray mist, may develop temporary signs and symp toms of localized irritation of the upper respiratory tract or skin; however, there are no substantiated cases of pulmonary fibrosis or systemic poisoning resulting from such exposure.

References

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2. Newhouse, M., D. McEvoy and D. Rosenthal: Fercutaneous Parasquat Alesomption. An Association with Cutaneous Lesions and Respiratory Failure Arch Dermatol. 114:1516 1519 (1978).

3. Waight. J.F. and RM. Wheater: Fatal Percutaneous Paraquat Leasoning. J Am Mest Assoc 242.472 (1979).

4. Levin, PJ. J. Klaff. A.G. Rose and A.D. Ferguson: l'ulmonary Effects of Contact Exposure to Paraquat- A Clinical and Experimental Study Thonix 34-150-160) (1979).

5. Rose, M.S., FA lock. LL Smith and I. Wyatt: l'araquit Accumu Lation. Fissure and Species Specificity. Biochem. Pharmac. 25 419 425 (1976)

6. Wyatt. 1.. A. W. Doss, D.C. Zavalla and LL. Smith: Infrabronchial Instillation of Paraqual in Rots. Lung Morphology and Retention Study Brit 4 ind. Med. MRAZ 48 (1981)

7. Zavalla. D.C. and M.L.. Khodes: An Effect of Paraquat on Lungs of Kablats: Its Implications in Smoking Contaminated Marijuana. Chest 74, 118 420 (1978).

8. Clark, D.G., T.F. McElligott and H.E. Weston: The Toxicity of Paraquat. Brit. J. Ind Med. 23:126 132 (1966).

9. Butler, C. and J. Kleinerman: Paraquat in the Rabbit Ibid. 28:67 71 (1971)

10. Mehani. S.: The Toxic Effects of Fataquat in Rabbits and itats. Ain Shams Med. J. 23.599 601 (1972).

11. Gage, J.C.: Toxicity of Paraquat and Diquat Aerosols Generated by a Size Sclective Cyclone. Effect of l'article Size Distribution. Brit J. Ind. Med. 25:301 314 (1968).

12. Smith. LL: Three Week Inhalation Study in Rats Exposed to an Aerosol of Paraqual Report No. ICI 254 7949, Huntingdon Research Center (June 8, 1979).

13. Idem: Three Week Inhalation Study in Rats Exposed to an Aerosol of Paraqual (Repeat Study). Report No. ICI 279-79476, Huntingdon Research Center (December 1979).

14. Idem: Assessment of Accumulation of Paraquat in the lungs. I Week Inhalation Study in Rats (15 Exposures). Report No. ICI 301/8037, Huntingdon Research Center (August 1980).

15. Swann, A.A.B.: Exposure of Spray Operators to Paraquat - Brit. J. Ind. Mrd 26.322 329 (1969).