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Daminozide, also known as aminozide, Alar, Kylar, SADH, B-995, B-nine,<ref name=AlarEPA_PFS_840630/> and DMASA,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is an organic compound which acts as a plant growth regulator.<ref name=AlarEPA_PFS_840630/> It was produced in the U.S. by the Uniroyal Chemical Company, Inc., (now integrated into the Chemtura CorporationTemplate:Not verified in body), which registered daminozide for use on fruits intended for human consumption in 1963. It was primarily used on apples until 1989, when the manufacturer voluntarily withdrew it after the U.S. Environmental Protection Agency proposed banning it based on concerns about cancer risks to consumers.<ref name="EPA1" /> In addition to apples and ornamental plants, Uniroyal also registered daminozide for use on cherries, peaches, pears, Concord grapes, tomato transplants, and peanut vines.
When used on fruit trees, daminozide affects flower bud initiation, fruit maturity, fruit firmness and coloring, preharvest drop and market quality of fruit at time of harvest and during storage.<ref name="EPA1">Template:Cite press release</ref> When consumed by mammals, daminozide is catabolised into succinic acid (a non-toxic general intermediate in primary metabolismTemplate:Citation needed) and 1,1-dimethylhydrazine (UDMH, a compound with a history of studies associating it with carcinogenic activity in animal models relevant to humans). Breakdown into these two compounds also occurs when the sprayed chemical residue remains on stored fruit, especially with higher temperatures and over longer time periods.<ref name="ZeiseJackson1991">Template:Cite book</ref>
In 1989, the EPA outlawed daminozide on U.S. food crops, but still allowed it for non-food crops like ornamental plants.<ref>Template:Cite report</ref> As of August 2022, daminozide appeared as severely restricted in its exports on the list of pesticides whose shipments were ineligible for export credit insurance under the Export–Import Bank of the United States.<ref name="EXIM_221108" />
ChemistryEdit
Template:Expand section While described by the FDA as an amino acid derivative,<ref name="AlarEPA_PFS_840630">Template:Cite report</ref> daminozide is more formally and correctly described as a dicarboxylic acid monohydrazide.<ref>The agent is neither synthesized from, not does it contain as component, any amino acid.Template:Citation needed</ref>Template:Citation needed It is the product of the condensation of succinic acid with 2,2-dimethylhydrazine,Template:Citation needed and in its pure form is a high-melting temperature water-soluble white crystalline solid.<ref name=AlarEPA_PFS_840630/>Template:Citation needed
Modes of actionEdit
Template:Expand section Daminozide is classified as a plant growth regulator, a chemical sprayed on fruit to regulate their growth.<ref name=EPA1/> When used on fruit trees, it affects flower bud initiation, fruit maturity, fruit firmness and coloring, and preharvest drop,Template:How which together make harvest easier and keep fruit from falling off the trees before they ripen; it also improves quality of fruit at time of harvest and during storage.<ref name=EPA1/>
Carcinogenicity of daminozide degradation productsEdit
When daminozide residue on fruit is consumed by mammalian species, it is catabolised into two chemical components, succinic acid (a non-toxic general intermediate in primary metabolismTemplate:Citation needed), and 1, 1-dimethylhydrazine ("unsymmetrical dimethylhydrazine", UDMH). Degradation into these products also occurs when the sprayed chemical residue remains on stored fruit, increasing with time and elevated temperature.<ref name="ZeiseJackson1991" /> UDMH has had a history of studies associating it with carcinogenic activity in animal models relevant to humans, beginning in the 1960s.<ref name="ZeiseJackson1991" />
U.S. campaign to ban AlarEdit
Template:Multiple issues In 1985, the EPA studied daminozide's effects on mice and hamsters, concluding that it was a "probable human carcinogen" with a dietary risk possibly as high as one cancer for every thousand people exposed, and proposed banning its use on food crops.<ref>Template:Citation</ref> They submitted the proposal to the Scientific Advisory Panel (SAP), which concluded that the tests were inadequate to determine the carcinogenicity of the tested substances.<ref name="x034">Template:Cite news</ref>
Later, in May 1989, Democrats Joseph Lieberman (D-CT) and Harry Reid (D-NV) held a press conferenceTemplate:Why in which the pesticide program at the FDA was accused of being "riddled with pro-industry bias", charging that 7 of 8 SAP members had worked as "consultants for the 'chemical industry'" — that the worst of them, after serving on the SAP (see below), had "later broke[n] conflict-of-interest laws", with career university academic toxicologists Wendell Kilgore and Christopher Wilkinson (29 years, UCal-Davis and 22 years, Cornell) being singled out as "possible violators of the [FDA] ethics code", with invitation to the "EP[A] inspector general [IG] to investigate".<ref name="MarshallScience890707">Template:Cite journal</ref> Marshall Elliot, writing for the News & Views section of the AAAS publication, Science, noted that these Senators' public scolding of SAP members—which was prompted by the FDA's "waffling on Alar"—led to the investigation of just these two academics by that agency's IG, and of forwarding of Kilgore's file to the U.S. Justice Department for review.<ref name = MarshallScience890707/> Marshall further noted that the event was being seen, in the months following, more for its forcing clarification of rules regarding
how much the government [can limit its]... more than 100,000 advisors, including scientists... who deal with issues ranging from biomedicine to arms control... [quotes spliced to clarify advisor roles] involvement with industry without isolating itself from the expertise it seeks,<ref name = MarshallScience890707/>
than for unearthing formal wrongdoing in the Alar case (wherein, after reversal of an earlier, similar conviction on appeal, no charges were ultimately broughtTemplate:Verify source).<ref name = MarshallScience890707/> In particular, the Senators alleged that Kilgore had a financial connection to Uniroyal, with Wilkinson and the other five being accused of having more general financial ties to the chemical industry;Template:Verify source<ref name="Rachel's">Template:Cite journalTemplate:Better source needed</ref>Template:Better source needed notably, the key formal contention was of possible violation of FDA ethics rules regarding limits to the "kind of consulting jobs that can be accepted after leaving an advisory panel" [emphasis in original source].<ref name = MarshallScience890707/>
The next year, the EPA retracted its proposed ban on Alar and required farmers to reduce its use by 50%.Template:Citation needed The American Academy of Pediatrics urged EPA to ban daminozide,Template:Citation needed and some manufacturers and supermarket chains announced they would not accept Alar-treated apples.<ref name="Rachel's" />Template:Better source needed
In a 1989 NYT opinion by Natural Resources Defense Council (NRDC) trustee John B. Oakes, regarding a two-year NRDC study peer-reviewed by an independent panel,<ref>Template:Cite report</ref> Oakes presented the report's argument that children ingesting daminozide in legally permissible quantities were at "intolerable risk" (from it and a wide variety of other potentially harmful chemicals); by their estimate, Oakes said, the "average pre-schooler's exposure to this carcinogen... result[s] in a cancer risk '240 times greater than the cancer risk considered acceptable by E.P.A. following a full lifetime of exposure.'"<ref>Template:Cite news</ref>Template:Better source needed In February, 1989, the CBS television program 60 Minutes broadcast a story about Alar that featured the NRDC report highlighting problems with the chemical.<ref name="Percival_etal_4th">Template:Cite book</ref><ref name="ShawLATimes940912">Template:Cite news</ref>
Later in 1989, the U.S. Environmental Protection Agency (EPA) decided to ban Alar on the grounds that "long-term exposure" posed "unacceptable risks to public health."Template:Quote without source However, in June 1989—before the EPA's preliminary decision to ban all food uses of Alar went into effect—Uniroyal, Alar's sole manufacturer, agreed to halt voluntarily all domestic sales of Alar for food uses.<ref name = Percival_etal_4th/><ref name="Gunset">Template:Cite news</ref> Hence, the consequences of CBS broadcast were swift and severe; as Percival, Schroeder, Miller, and Leape note in review of legal aspects in their Environmental Regulation text,
"[t]he denouement... came quickly. Alar was removed from the apple market by its manufacturer, not because of regulatory requirements imposed by the EPA, but because of consumer pressure"
in particular, the "rapid decline in apple consumption that followed the "60 Minutes" report"<ref name = Percival_etal_4th/> As the Chicago Tribune noted at that time, Alar's export was not prohibited, such that Uniroyal could continue its sales in about 70 countries, which led critics to note that Americans still faced exposure (via imported fruit and juice).<ref name="Gunset" /> However, as of August 2022, daminozide/alar was appearing as a "severely restricted" entry on the List of Banned and Severely Restricted Pesticides Under the Prior Informed Consent (PIC) Program of the Export-Import Bank of the United States, making its shipments ineligible for export credit insurance.<ref name="EXIM_221108">{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
BacklashEdit
In November 1990, Washington apple growers filed a lawsuit in Yakima County Superior Court against CBS, NRDC and Fenton Communications (hired by NRDC to publicize their report on Alar)<ref name="Carlson">Template:Cite news</ref> claiming that unfair business practices (product disparagement in particular) cost them $100 million.<ref name="Trib">Template:Cite news</ref><ref>Template:Cite news</ref><ref>Template:Cite news</ref> The suit was moved from state to federal court at the request of CBS.<ref>Template:Cite news</ref> U.S. District Judge William Fremming Nielsen ruled in 1993 that the apple growers had not proved their case,<ref>Template:Cite newsTemplate:Better source needed</ref>Template:Better source needed and it was subsequently dismissed by the United States Court of Appeals for the Ninth Circuit.<ref name="Bernard">Template:Cite newsTemplate:Third-party inline</ref>Template:Better source needed
Elizabeth Whelan and her organization, the American Council on Science and Health (ACSH), which had received $25,000 from Alar's manufacturer,<ref name="Neff2005">Template:Cite journal</ref> stated that Alar and its breakdown product UDMH had not been shown to be carcinogenic.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> During a 1990 speech at Hillsdale College, Whelan said that groups like the NRDC were ignoring a basic principle of toxicology: the dose makes the poison. "It is an egregious departure from science and logic when a substance is labeled 'cancer-causing' based on a response in a single animal study using high doses of a test material", she said.<ref name="Imprimis">Template:Cite journal</ref>Template:Page needed
Current viewsEdit
Template:Cite check Taken together, the complexity of the problem of assigning risk to this agent—the debate over assumptions concerning risks from early-in-life exposure, the principal role of a decomposition product rather than the agent itself in determining its long-term toxicity, the generation of that product both abiotically and through metabolism after consumption, as well as challenges in determining appropriate "subpopulations for study, representative parameters of the potency distribution, and corrections for bioassay length"<ref name = ZeiseJackson1991/>—have had as a consequence that disagreement and controversy remain about the safety of daminozide and the appropriateness of responses to it in its history.<ref name = ShawLATimes940912/><ref name = ZeiseJackson1991/>Template:Update afterTemplate:Citation needed
Consumers Union did its own analyses and estimated that the human lifetime cancer risk was 5 cases per million, as compared to the previously reported figure of 50 per million.Template:Citation needed (The EPA had argued for a level of lifetime cancer risk of 1 per million to be the highest acceptable, in this type of case.Template:Clarify<ref>Template:Cite journal</ref>Template:Verify source) On the other hand, representatives of the California Department of Health Services are on record as of 1991 stating that "the plausible estimates of risk, derived from conservative, reasonable assumptions, exceed those developed by EPA and NRDC".<ref name = ZeiseJackson1991/> As late as 1995, results continued to appear (e.g., from a medium-term carcinogenicity assay approved for use by the ICH)<ref>Template:Cite journal</ref>—supporting insignificant levels of "carcinogenicity of daminozide, alone or in combination with... 1,1-dimethylhydrazine".<ref>Template:Cite journal</ref>Template:Update after
As of 2005, daminozide remained classified as a probable human carcinogen by the EPA, and listed as a known carcinogen under California's Prop 65.<ref name=Neff2005/>Template:Update after
ReferencesEdit
Further readingEdit
- Template:Cite journal This is a formal response of Edward Groth III of the Consumers Union, reflecting the back-and-forth debate on this matter, at the highest levels of American science. See also the original Koshland editorial, and other responses on the pages following this.
- Template:Cite journal This article is Science's formal reporting, months after, regarding the Lieberman-Reid hearings into the ethics and ties of the EPA SAP to the chemical manufacturing industry, a hearing which resulted in institutional reviews of the rules (but no formal charges against any SAP member).
- {{#invoke:citation/CS1|citation
|CitationClass=web }} This extensive self-published work (this the first of a four-part series) is an attempt on the part of a former NRDC staffer to correct what she perceives to be the false narrative that has emerged, that pulling Alar from the market was an overreaction based on incomplete or poor science.