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Ribicoff asked Carson to elaborate on her call for additional research into genetic effects at the federal level. Carson felt that the FDA should have a department of genetics or at least a small staff of geneticists to determine genetic effects, which she noted could be quite independent from the toxic effect. Carson’s reasoning flowed from her knowledge of medical genetics, which had shown that many human defects and illnesses could result from apparently slight damage to the chromosomes: “But those apparently slight genetic changes cause a whole group of diseases or defects, especially of congenital defects, very often including mental deficiencies.”51 From this point, Carson shifted back to chemical toxicology and the fact that certain chemicals, including some pesticides, also caused chromosomal damage. Juxtaposing these related fields brought Carson to her conclusion: “Now I think those two fields of study ought to be gotten together. We should find out whether the pesticide chemicals in the concentrations in which they are used or at the levels to which they may build up in the human body, are capable of causing these defects and these illnesses.”52 Genetic toxicology was in its infancy when Carson made this recommendation in 1963.53
At times Carson called upon the committee to deepen its probe of the pesticides industry and its implications for Americans. For example, Ribicoff noted that many pesticides were intended for home and garden use, but that before the publication of Silent Spring individuals had little or no appreciation of their potential dangers. Rather than beginning at the point of use, Carson suggested that the committee might give attention to the type of advertising that introduced consumers to these chemicals. She stated: “I think at the present time and in the past there has been too little to warn the consumer that he is buying and using a very hazardous substance. In fact, the tone of many advertisements of course is quite the contrary.”54 She hoped that the committee would correct this problem of minimizing risk in advertisements. By way of conclusion, Senator James B. Pearson of Kansas summarized Carson’s various arguments: “I think from this report and from what you have said that it justifies the work of this committee. We ought not to minimize any dangers, and we should seek an objective analysis, which I have great confidence the chairman will provide. We must not only not overlook dangers, but also must seek to allay any fears the public may have that will come about from this voluminous amount of testimony and hearings that we are conducting.”55
To the extent that Silent Spring brought the unintended consequences of chemical insecticides to the attention of Americans, Carson’s testimony to the Ribicoff subcommittee on interagency coordination underscored the importance of the soft-spoken biologist in the quest to understand the risks of pesticides and helped to place their benefits in context, much like the CBS report a few weeks prior. Carson succumbed to cancer some ten months after appearing before the committee, but the hearings continued, and to mark the sad occasion Ribicoff read a tribute to Carson: “After Rachel Carson brought her message of concern to the public, it was no longer possible to consider only the benefits of manmade pollution without weighing the risks. It was no longer possible to build a new factory without being concerned about air pollution, a nuclear reactor without being concerned about water pollution, or a new pesticide to make food more abundant without being concerned about the health of wildlife and even people. She was no fanatic trying to wish away the advantages of the 20th century. She was a humanitarian, insisting that man weigh carefully the consequences of his modern technology and strike a balance that will preserve the wonder of nature in the 21st century.”56 Ribicoff concluded: “Today we mourn a great lady. All mankind is in her debt.”57
Like Carson, both the PSAC and the Committee on Interagency Coordination explored the toxicity of the major classes of insecticides with particular emphasis on the chlorinated hydrocarbons like DDT. The PSAC also noted the risks of organophosphates, such as parathion: “Most organic phosphorus insecticides have relatively high acute toxicities and have caused many fatal and nonfatal poisonings in man. In cases of poisoning, removal from exposure to the compound usually permits rapid recovery. Many of them are degraded rapidly and thus seldom persist in the environment, but some, such as parathion, have persisted for months in soils and have recently been found in trace amounts in water drawn from deep wells.”58 High toxicity and rapid disintegration in the environment were the characteristics that made organophosphates useful as insecticides; high toxicity also made them highly dangerous to use. The PSAC included among its recommendations that the FDA should expand its total diet studies on chlorinated hydrocarbons to include data on organophosphates, herbicides, and carbamates in populated areas where they are widely used. The PSAC also listed parathion among the commonly used chemicals that the FDA should include in its review of residue tolerances and the experimental studies on which they are based.59
Later George Larrick, commisioner of the FDA, elaborated on the agency’s efforts to develop meaningful residue tolerances for organophosphates, noting that cholinesterase inhibitors could potentiate when used together. The FDA stopped issuing tolerances in that area and called upon manufacturers to test not only the toxicity of the single pesticide but also the multiple combinations that might be used. Despite increased levels of testing at the FDA, universities, and corporations, Larrick acknowledged the limitations of available information: “The total knowledge, the biological experience and knowledge in this field is not great enough at this time to permit anybody to say with honesty that we know enough about it to be very sure that there are not some synergistic adverse effects possible, and certainly we need to step up research, as Dr. Wiesner said, very extensively in this field to insure a greater protective job.”60
Not all of the witnesses were as sanguine when it came to the continued use of organophosphate insecticides. Theron G. Randolph, formerly chief of the Allergy Clinic at the University of Michigan Medical School, argued that some individuals became sensitized to certain chemicals as a result of cumulative exposures. This possibility of sensitization led to Randolph’s first recommendation (of six): “Persistent insecticides (chlorinated and related hydrocarbons); highly toxic insecticides (organophosphorous material) and biological insecticides which sensitize readily (Pyrethrum) should not be employed in the home or incorporated into other materials for home use.”61 Randolph did not indicate that he was aware that this recommendation would have effectively banned the three major classes of insecticides from household use.
Other researchers cited data that supported Randolph’s recommendations. Dr. Irma West, from the Bureau of Occupational Health in the California Department of Public Health placed the risks of organophosphates in the context of other hazardous classes of insecticides: “It is of interest to note that in the past decade in California there have been three different groups of pesticides primarily involved in fatal effects upon humans and wildlife: for children it has been arsenic, for workers organic phosphates, and for wildlife the chlorinated hydrocarbons.”62 To bolster her case against organophosphate insecticides, West cited statistics from the California Bureau of Occupational Health. She interpreted the data as follows: “While organic phosphate pesticides represented about 80 percent of the total reports, they constituted nearly three-quarters of the 268 reports of systemic poisonings, thus indicating the hazardous nature of the organic phosphate pesticides.”63 An analysis of 911 reports of occupational disease attributed to pesticides in California in 1961 revealed that parathion was by far the most frequently reported organic phosphate, accounting for 110 of the 254 reports of occupational illness attributed to organophosphates followed by phosdrin (29 reports) and malathion (24 reports). DDT and other chlorinated hydrocarbons (chlordane, lindane, and keltane) accounted for 34 reports, and the more toxic insecticides in the class (endrin, aldrin, dieldrin, and toxaphene) yielded just 7 reports.
Such data convinced the California Department of Public Health to recommend mandatory medical supervision, including routine cholinesterase tests for all people working with toxic or
ganophosphates. In fact, the state’s Department for Industrial Relations adopted the recommendations in their Safety Orders for Agricultural Operations in November 1961. The Safety Orders required employers to engage a licensed physician to provide medical supervision whenever workers were spreading, spraying, dusting, or making other application or formulation of toxic organic phosphate pesticides.64 The orders further defined medical supervision to include advance planning for prompt care of organophosphate poisoning and cholinesterase determinations or other recognized medical tests before exposure and if necessary after exposure as well.
Not all organophosphates reached the point where they could be marketed to the public. Julius E. Johnson, the manager of Bioproducts for Dow Chemical noted several examples of organophosphates, among others, that were eliminated from further development as a result of toxicological analysis. Dow abandoned several organophosphates after determining that they were highly toxic to mammals via skin absorption or ingestion, with LD50s to rats in the range of one to two mg/kg of body weight.65
Nevertheless, organophosphate insecticides posed considerable risks, even in cases in which established guidelines were followed. One epidemic in California involved a recorded ninety-four pickers, but there was no evidence that the recommended fourteen-day interval between spraying and harvesting was violated. Researchers hypothesized that the parathion in use was somehow altered to one or more cholinesterase-inhibiting compounds of considerably greater toxicity, and they suspected paraoxon as the most likely compound. It also seemed likely that the ninety-four pickers, who sought medical attention, reflected a fraction of the total exposed population that would have shown evidence of poisoning, if they had been studied.66
When Bert J. Vos, deputy director, Division of Pharmacology at the FDA, appeared before the committee, Ribicoff took the opportunity to return to no-effect level, which the Wiesner Report addressed specifically, noting critically that the FDA had set tolerances for compounds (notably dieldrin, aldrin, heptachlor, and chlordane) even though a no-effect level for animals had never been determined. Ribicoff asked Vos to explain how the FDA had determined tolerances for these and other compounds in the absence of a no-effect level. In response, Vos gave a rambling description of a process that drew on the overall picture of toxicity, comparing the compound to related compounds for which no-effect levels had been determined. Ribicoff asked how he could make such a determination without the no-effect level. Vos attempted to clarify with this statement: “As I said, the tolerance was arrived at by comparing the level at which effect did occur, the severity of the effect, and comparing that with other pesticides which produced similar effects, comparing the levels. The ones at which a no-effect level was not reached, we, you might say, extrapolated on the basis of the way in which the severity effect was at higher levels.”67 For Ribicoff, there was a simpler description of the process: “In other words, what you are doing is guessing?”68 Vos initially stood firm, but he eventually conceded the point.69
Later Ribicoff raised the issue of the no-effect level with several representatives from companies that manufactured chemicals. John P. Frawley, chief toxicologist in the Medical Department of the Hercules Powder Company, and formerly assistant chief of the Chronic Toxicity Branch at the FDA70, was describing the development of the no-effect level when Ribicoff interjected that if scientists did not perform tests and the chemicals did in fact have genetic effects, was there not the possibility of producing another thalidomide? Frawley answered this question at length by dismissing the comparison with thalidomide since the infamous tranquilizer was used at pharmacologically active levels. For pesticides, scientists relied on the no-effect level: “With pesticides, we have demonstrated the no-effect level by every tool that we can bring to our command today. Then we administer or permit in the environment of man something which is a small fraction of that no-effect level in the animal.” Dow’s Johnson clarified Frawley’s response by noting that for hypnosis, thalidomide had a dosage range between 50 and 200 milligrams per person. For contrast, Johnson cited Hayes, who had said that DDT would amount to 0.284 milligrams per person. The 50-milligram dosage level would be an intake of 200 times as much and the 200-milligram level would be almost 1,000 times as much intake. With this comparison, Johnson hoped to illustrate the difference between an effect level of a drug like thalidomide and a very minute trace level of a pesticide like DDT.71
By 1963, as Nancy Langston has shown, thalidomide stood at the center of a major controversy in pharmaceutical regulation.72 A European company, Chemie Grünenthal, first synthesized thalidomide in 1954 as part of a search for new antibiotics.73 The new drug revealed no antibiotic properties, but the company patented it and distributed samples to doctors in West Germany and Switzerland. Strangely, Chemie Grünenthal had not developed a scientific protocol to monitor results or to conduct a systematic follow-up, but when patients reported thalidomide’s sedative effects, the company discovered a market for the drug. Even before thalidomide was released to the market, there was a report of a baby born without ears after its mother used thalidomide in pregnancy. Nevertheless, on the basis of reports that the drug soothed nausea in pregnancy, Chemie Grünenthal marketed the drug for pregnant women, touting it as the “best drug for pregnant women and nursing mothers,” despite a complete lack of studies to consider thalidomide’s fetal effects.
When the Richardson-Merrell Company bought the U.S. license for thalidomide in 1960, it submitted a New Drug Application to the FDA. Frances Kelsey, Geiling’s former student and colleague at the Tox Lab, had recently taken a position at the FDA, and she found the thalidomide application troubling on two grounds. First, the drug’s “curious lack of toxicity” caused her to question the company’s safety data. Second, there was an absence of good evidence on its relation to metabolism and excretion. Kelsey rejected Richardson-Merrell’s New Drug Application for thalidomide. For months she had to withstand the badgering of the company as it tried to convince Kelsey (and her superiors) to approve the application. In November 1961, reports concerning European mothers who had taken thalidomide during pregnancy began to circulate: their babies had been born with severe birth defects. Kelsey noted cases of children born with hands and feet attached directly to the torso; others were born with limbless trunks; and still others were born with just a head and torso.74 Kelsey’s colleague confirmed the European reports and testified before Congress, which helped Kelsey to block the approval of thalidomide in the U.S. Despite mounting evidence, FDA Commissioner Larrick failed to take action until July 23, 1962, eight months after Richardson-Merrell notified the FDA that thalidomide had been withdrawn from the German market. An investigation revealed that both Chemie Grünenthal and Richardson-Merrell had attempted to deceive regulators. For the part she played in keeping thalidomide off the market in the U.S., Frances Kelsey received the President’s Award for Distinguished Federal Civilian Service from President Kennedy. Tragically, tens of thousands of Americans had received thalidomide as Richardson-Merrell had distributed the drug to more than 1,200 physicians for “investigational use.” More than 20,000 patients received more than 2.5 million pills during these trials. Most of the exposed women were never notified of the dangers of birth defects.75
In drawing a distinction between the cases of thalidomide and pesticides, Frawley and Johnson identified the critical difference: women had been exposed to thalidomide at therapeutic levels, which is to say levels much higher than those found in pesticides, except in extreme cases of acute exposure. Ribicoff redirected the discussion back to the no-effect level by asking if the scientists believed that the product should not go on the market until a no-effect level had been established. Frawley immediately agreed, but Johnson’s response was more deliberate, calling for a no-effect level in significant experiments that have a real bearing on the ultimate use of the product. When Ribicoff pressed him for further clarification, Johnson suggested experiments that would indicate such hazards as reproductive effects, or kidney damage, o
r liver damage. Ribicoff interjected to ask about skin irritation or eye irritation as a potential effect, but Johnson compartmentalized skin irritation as a handling hazard distinct from effects of long-term exposures to minute dosages. Ribicoff asked two other industry representatives, but neither was a toxicologist by training and both deferred to the opinions voiced by Frawley and Johnson.
Nevertheless, not all representatives of the pesticides industry shared Frawley’s and Johnson’s view of the no-effect level. Dr. Edmund F. Feichtmeir, manager of product application, Agricultural Research Division at Shell Development Company stolidly evaded and countered questioning regarding the no-effect level from Ribicoff. Ribicoff cited (as Exhibit 126) the definition of the no-effect level (as prepared by FDA). Specifically, the FDA defined the level as follows: “The ‘no-effect’ level may be defined as that dosage of the test substance which produces no adverse effect as determined by conventional methods.”76 In more technical terms, the FDA related the no-effect level to the LD50: “In the determination of an LD-50, for example, the LD-0 can be considered as the ‘no-effect’ dose under the conditions of this type of study.”77 In determining a chronic effect, no-effect levels could be assigned to a number of end points: mortality rate in treated versus controls, growth rate in treated versus controls, organ/body weight ratios, inanition, deposition in the tissues, cholinesterase inhibition, histopathology, demyelination, and toxic effect on the fetus. Based on this definition and the statement regarding no-effect levels in the PSAC report (see above), Ribicoff asked Feichtmeir whether it was true that a no-effect level had not been established for dieldrin, one of the stronger chlorinated hydro-carbons sold by Shell. Initially Feichtmeir acknowledged that it was true, but then he proceeded to qualify his statement noting that he was not in a position to say whether it was a no-effect level or not. He concluded that consultants and the FDA had deemed dieldrin safe, and he deferred to their designation.