Does the NAS Report Miss the Point About What Caused the Havana Syndrome?
From the beginning the Havana Syndrome story has been mired in politics.
While the science is inconclusive, some factual bilateral base lines should be kept in mind:
1) Only US and then Canadian embassy personnel were affected. The initial targets were reported to be US intelligence people, not diplomats. No other embassies, nor the Cuban population, encountered similar medical problems.
2) The attacks took place at several discreet periods that seemed to have a political or strategic logic. (They began in December 2016 creating a new atmosphere of conflict for incoming Trump officials, escalated in April when it seemed that Trump was not going to do anything to fulfill his harsh campaign promises in Miami, and were renewed in August after it was obvious that the only thing achieved in June was a hard line speech).
3) The attacks were on residences (houses or hotel rooms), not on the embassy buildings.
4) The official US response to the attacks was to surrender not to fight. Although US foreign service personnel officially recommended diplomats remain despite risks, the Secretary of State withdrew most US embassy and consular staff and forced Cuba to withdraw most of its staff from Washington. Senator Rubio had been pushing to completely close the embassies.
5) After the US gutted its capabilities, the attacks ceased. Remaining US personnel suffered no additional assaults.
6) The Cubans were extremely cooperative hosting several FBI delegations until it became obvious the US was not reciprocating with information. According to Reuters, “U.S. officials say off the record they cannot cooperate with Cuba on such a sensitive investigation where its Communist government has a strong interest in the outcome.”
7) The Cubans then took the public position that the problem was created for political reasons or was psychosomatic.
8) Most recently the Cuban scientific response to the NAS was more nuanced: “Cuba’s Academy of Sciences disagrees with the final conclusion regarding the causes of the ailments,” the academy said in a statement read to journalists by its President Luis Velazquez. Velazquez… said the “investigation about these health ailments has suffered from a lack of fluid communication between U.S. and Cuban scientists.”
9) This suggests that if the Biden Administration is prepared to collaborate seriously, Cuba will also.
10) The NAS study has replaced one unproven science fiction story with another. Occam’s razor suggests a known technology which can be undertaken covertly, chemical neurotoxins, the Canadian thesis, is more likely, especially if direct application rather than the unintended consequence of insecticide is considered.
11) The crucial factors are motive, agency and ability. The Russians and Cuban Americans had motive to destroy the Obama opening. Each had agency, the ability to act either with some Cuban cover or within the U.S. Embassy envelope. Only the Cuban Americans had a motive to attack the Canadians, the long despised largest source of tourists and the biggest foreign investor. However only the Russians have the experience and resources to use chemical neurotoxins so widely.
The onset of diverse symptoms was so unlikely and without an obvious explanation that the initial US response in the last months of the Obama Administration was to not say anything. When the complaints of affected staff forced the issue to be acknowledged, a series of theories surfaced in on-line publications and the New York Times. At first it was a mysterious unheard of acoustic weapon, then it was microwaves, now described as “directed, pulsed radiofrequency energy”.
After months of government mandated work, the National Academy of Sciences produced a report in August that clarified little and was kept secret for four months. But as the State Department said, “each possible cause remains speculative”. NBC News reported that, “Although it praised the National Academies of Sciences for undertaking the effort, the State Department offered a long list of ‘challenges of their study’ and limitations in the data the academies were given access to, suggesting that the report should not be viewed as conclusive."
I have pasted below comments I have received from a member of the Canadian team about the NAS report, largely justifying their original case that insecticide was responsible. Such an explanation has the benefit of being able to conclude the medical problems were an unintended consequence so no one should be held responsible. However that does not fit the anecdotal account by the top US diplomat in Havana and the NAS report that such abnormal spraying was not done at the residences of Americans.
His response to my questioning the insecticide thesis was:
Topical application either incidental or intentional of OP poisons will lead to the same sickness. We suspected more the relatively high dose / picture of agriculture pesticides since I saw that myself in the diplomats houses when I went to Havana as part of the research study. We cannot rule out very low dose of a more toxic agent that the Russians (for example) are using. According to Navalny, his wife Yulia has very similar symptoms to his, but to a lesser extent 2 weeks before he was poisoned. He claims she was poisoned first. We will never know in her case nor the Americans - as blood was not saved immediately after the acute event (another mishandling of the whole case by the State Department).
We don’t really know for sure, unfortunately. If fumigation / toxin exposure is the cause, at least we can stop that exposure.
These comments should not be distributed publicly but the source is prepared to personally respond to questions.
As you know, the Dalhousie team tested the Canadian diplomats, and without having all details I cannot rule out the possibility that the Americans have a different illness. The authors also agree that “Multiple kinds of mechanisms might contribute to the observed phenomena in the Department of State (DOS) personnel.” And specifically, that the “the chronic symptoms that were reported are often seen in patients after head trauma, as a result of chemical exposure, infectious diseases, or stress in a hostile environment.” (Page 17).
It seems that the committee was considering directed radio frequency energy mainly due to “the sudden onset of a perceived loud sound, a sensation of intense pressure or vibration in the head, and pain in the ear or more diffusely in the head”. I agree that this presentation is not typical to pesticides exposure, but importantly, such presentation was not reported by most Canadian diplomats (except one). What I find strange is that while the authors admit that “only a subset of individuals who reported suffering from the late set of generally more common signs and symptoms, also described the more distinctive early set and in particular, the sudden onset of a directional or location-specific loud noise, pressure or pain,” (Page 12) it is not mentioned how many of the American diplomas did report the acute symptoms. I think it is critical to know (from the over 30 who reported symptoms) whether 1, 5, or 25 described in real-time the sudden onset of “a directional or location-specific loud noise, pressure or pain”. This number has never been reported.
The authors thus admit that it was “difficult to know with certainty that all cases were due to the same cause(s), and in particular, whether the individuals with only the chronic set of signs and symptoms suffered from the same cause(s) and etiologic mechanisms as those who reported the initial, sudden onset set of signs and symptoms.”
With regards to the NAS evaluation of our study and the “toxin hypothesis”, the authors agree that "The potential for exposure of U.S. Embassy personnel to these insecticides was quite high." (Page 21)
And that “it is highly likely that U.S. Embassy personnel were exposed to OPs either when they were in public spaces or via overspray that drifted from public spaces into U.S. Embassy offices and residences”
The authors confirm that they cannot rule out over-exposure in the American diplomats since
“AChE activity was not measured in blood from U.S. Embassy personnel.”
The NAS report also states that, “Another concern with the Dalhousie measurements is that AChE levels should always be compared to the established reference values of the clinical laboratory in which the measurements are performed.” This is a strange criticism from a scientific committee. Simply put, our approach proceeded according to how such scientific research is done: by comparing two groups of individuals and running statistical analysis. Their criticism of the method of control groups is especially strange in light of the NAS committee’s repeated critique that the studies conducted were missing precisely such a “control group” when it came to testing US diplomats (Pages 12 and 15). As for their preferred comparison method for AChE levels, no such established reference values exist in our clinical laboratory (or to the best of our knowledge elsewhere in Canada), so we had to use a different, but completely valid, scientific approach.
Another NAS criticism of the Dalhousie report: “A second reason is that the number of Canadian personnel with detectable levels of temephos or 3-PBA was much smaller than the number of individuals with symptoms.” This is a misreading of our work, as our report showed traces of temephos or 3-PBA in the majority of exposed individuals: “Temephos was detected in six of ten remotely exposed individuals, compared to one recently exposed individual and none of the controls (P<0.001). 3-PBA was found in the majority (62%) of exposed individuals” (Page 10, Friedmaan et al., 2019).
The NAS authors admit that “it is not possible to determine whether exposures [to OPs or pyrethroids) were at levels that might reasonably cause toxic effects, particularly in vulnerable individuals.” (Page 22).
They also admit that the symptoms of individuals affected by certain OPs and insecticides are consistent with the chronic symptoms reported by the US diplomats: “With regards to the overlap of symptoms between chemical exposures and the Havana cases, epidemiologic and clinical studies have linked occupational or environmental chemical (including OP and pyrethroid insecticide) exposures to a subset of the distinctive early phase symptoms and many of the nonspecific chronic problems suffered by some of the U.S. Embassy Havana cases.”
The committee summarizes that part of the report by writing: “the committee could not rule out the possibility, although slight, that exposure to insecticides, particularly OPs, increased susceptibility to the triggering factor(s).” They also say that “differential exposure to insecticides amongst affected individuals may have contributed to the clinical heterogeneity of the acute symptoms noted in Havana cases,” and finally “The committee also finds it plausible that subacute or chronic OP and/or pyrethroid exposures contributed to the nonspecific chronic symptoms observed in affected U.S. Embassy personnel.” (Page 23). I could not agree more.
I also found it surprising that the committee ignored the results of what was likely the most objective test of American diplomats, namely the visual test undertaken shortly after exposure: “average pupil area was significantly smaller in the Havana affected group” (Balaban, 2020). A small pupil, also known as miosis, is one of the most classical signs of organophosphate poisoning.
A final thought: one key way to further confirm or reject the insecticidal hypothesis is to test Cubans who were similarly exposed, including those living in nearby areas, working at the embassies (or residents), or those who are fumigating. We have initiated such a collaborative study with Cuban scientists (unfortunately the study was halted due to COVID-19). Unfortunately, our American colleagues were not interested in such collaboration.
Efficacy and outcomes of lipid resuscitation on organophosphate poisoning patients: A systematic review and meta-analysis. Yu S, Yu S, Zhang L, Gao Y, Walline J, Lu X, Ma Y, Zhu H, Yu X, Li Y.Am J Emerg Med. 2019 Sep;37(9):1611-1617. doi: 10.1016/j.ajem.2018.11.022. Epub 2018 Nov 17.PMID: 30527914
Obesity-related acetylcholinesterase elevation is reversed following laparoscopic sleeve gastrectomy. Shenhar-Tsarfaty S, Sherf-Dagan S, Berman G, Webb M, Raziel A, Keidar A, Goitein D, Sakran N, Zwang E, Shapira I, Zeltser D, Berliner S, Rogowski O, Shibolet O, Zelber-Sagi S.Int J Obes (Lond). 2019 Feb;43(2):297-305. doi: 10.1038/s41366-018-0014-4. Epub 2018 Feb 3.PMID: 29491490
Prevalence of Abnormal Serum Cholinesterase and Associated Symptoms from Pesticide Exposure among Agricultural Workers in the South of Thailand. Guytingco A, Thepaksorn P, Neitzel RL.J Agromedicine. 2018;23(3):270-278. doi: 10.1080/1059924X.2018.1470049.PMID: 30047860
Acetylcholinesterase Activity Measurement and Clinical Features of Delirium. Jackson TA, Moorey HC, Sheehan B, Maclullich AM, Gladman JR, Lord JM.Dement Geriatr Cogn Disord. 2017;43(1-2):29-37.
Decline in serum cholinesterase activities predicts 2-year major adverse cardiac events.
Arbel Y, Shenhar-Tsarfaty S, Waiskopf N, Finkelstein A, Halkin A, Revivo M, Berliner S, Herz I, Shapira I, Keren G, Soreq H, Banai S.Mol Med. 2014 Feb 12;20(1):38-45. doi: 10.2119/molmed.2013.00139. Evaluation of neurotoxicity of repeated dermal application of chlorpyrifos on hippocampus of adult mice. Mitra NK, Siong HH, Nadarajah VD.Ann Agric Environ Med. 2008;15(2):211-6.
Acetylcholine terase activity in veterans of the first Gulf War. Concato J, Aslan M, Palmisano MM, Doebbeling CC, Peduzzi P, Ofek K, Soreq H, Doebbeling B.J Investig Med. 2007 Nov;55(7):360-7. doi: 10.2310/6650.2007.00016.
Organophosphate poisoning: 10 years of experience in southern Taiwan. Tsai JR, Sheu CC, Cheng MH, Hung JY, Wang CS, Chong IW, Huang MS, Hwang JJ.Kaohsiung J Med Sci. 2007 Mar;23(3):112-9. doi: 10.1016/S1607-551X(09)70385-7.
Distinctive Convergence Eye Movements in an Acquired Neurosensory Dysfunction. Carey D Balaban 1 2 3 4, Mikhaylo Szczupak 5, Alexander Kiderman 6, Bonnie E Levin 7, Michael E Hoffer 5 8 Front Neurol. 2020 Jun 16;11:469. doi: 10.3389/fneur.2020.00469. eCollection 2020.
The full Canadian report can be accessed here: https://cubapeopletopeople.blogspot.com/2019/11/cause-of-havana-syndrome-identified-by.html
Section of NAS Report that addresses the Canadian findings
Sources of Information
DOS asked the committee to consider the plausibility of organophosphate (OP) or
pyrethroid insecticide exposure as a cause of the clinical signs/symptoms observed in U.S.
Embassy personnel in Havana. This possible cause was raised by Canadian investigators who
reported decreased cholinesterase activity, temephos (an OP), and pyrethroid metabolites in
blood samples collected from some Canadian Embassy personnel and Canadian tourists who
were in Havana during the same period as the affected U.S. Embassy personnel. Additionally,
the timing of some cases in U.S. Embassy personnel coincided with widespread spraying of OP
and pyrethroid insecticides in Cuba in 2016 to mitigate spread of Zika virus by mosquitos.
To address the plausibility of the OP/pyrethroid insecticide hypothesis, the committee
examined five sources of information: (1) the Research Report, “Havana Syndrome:
Neuroanatomical and Neurofunctional Assessment in Acquired Brain Injury Due to Unknown
Etiology” (Friedman et al., 2019); (2) formal presentations to the committee by Claire Huson
(DOS Office of Safety, Health, and Environmental Management), Cynthia Calkin and Alon
Friedman (Dalhousie University Faculty of Medicine), Marion Ehrich (Virginia-Maryland
College of Veterinary Medicine), and Nick Buckley (University of Sydney); (3) feedback
provided during a question and answer session with DOS Bureau of Medical Services staff; (4)
the National Toxicology Program publication, “Systematic review of long-term neurological
effects following acute exposure to the organophosphorus nerve agent sarin,” (NTP, 2019); and
(5) peer-reviewed scientific literature.
The committee considered three general issues: (1) What is the strength of the evidence
that affected individuals were exposed to OP or pyrethroid insecticides?; (2) Were exposures at
levels that might be expected to cause toxic effects?; and (3) How similar are the signs and
symptoms of acute, subacute, or chronic exposures to OP or pyrethroid insecticides to the
distinctive acute signs and symptoms and the less specific chronic signs and symptoms
associated with cases from Havana?
Assessment and Findings
With respect to the question of exposure, information presented by Claire Huson
regarding the DOS Integrated Pest Management (IPM) program indicated that pyrethroids
(lambda cyhalothrin, cyfluthrin, permethrin, and cypermethrin) were used in U.S. Embassy
offices and residences in Havana; thus, the potential for exposure of U.S. Embassy personnel to
these insecticides was quite high. OPs were not included in the IPM program and it is DOS IPM policy not to allow outside contractors to apply pesticides in U.S. Embassy offices or residences.
Consistent with this information, the committee heard in a question and answer session with
DOS medical staff that OPs were not detected in environmental samples collected from the
residences of U.S. Embassy personnel some months after the incidence of unexplained illnesses.
However, this information does not rule out the possibility that U.S. Embassy personnel were
exposed to OPs in their residences proximal to the onset of symptoms because OPs are relatively
short-lived in the environment (half-life of several days in the outdoor environment and weeks to
months in the indoor environment depending on dust levels, light, and humidity). Moreover,
information provided by presenters from Dalhousie University indicated widespread heavy
spraying of OPs (including the OP chlorpyrifos) and pyrethroids throughout Cuba to prevent the
spread of Zika virus by mosquitos. If the images of pesticide spraying shown in the formal
presentations to the committee were reflective of actual conditions in Havana, it is highly likely
that U.S. Embassy personnel were exposed to OPs either when they were in public spaces or via
overspray that drifted from public spaces into U.S. Embassy offices and residences. As an aside,
targeted exposures of individuals to OPs are also possible, as illustrated by the assassination of
Kim Jong-nam, half-brother of North Korean leader Kim Jong-un, who died after two women
allegedly applied OP nerve agent to his skin in the Kuala Lumpur airport on February 13, 2017,
and by the attempted assassination of a former Russian spy and his daughter in Great Britain in
2018. However, these individuals showed acute symptoms of cholinergic poisoning associated
with their exposure to OPs.
OP exposure is also monitored by measuring AChE activity in blood samples because OP
insecticides inhibit AChE. AChE activity was not measured in blood from U.S. Embassy
personnel. The Dalhousie University research team presented data they believed demonstrated
significantly decreased AChE activity in at least a subset of Canadian Embassy personnel and
Canadian tourists who were in Havana during the same time as affected U.S. Embassy personnel.
Based on these data and targeted analysis of OPs and pyrethroid metabolites in serum samples
that identified the OP temephos and the pyrethroid metabolite 3-PBA in blood from a subset of
individuals (although the overlap between individuals with AChE inhibition and detectable
OPs/pyrethroids is not clear), the Dalhousie University group developed a working hypothesis
that neurological effects were due to chronic low level cholinesterase inhibitor toxicity. These
data cannot, however, be considered supportive of this hypothesis. One reason, based on
information presented to the committee, is that the Dalhousie group measured AChE activity in
serum/plasma samples. However, AChE is a membrane-bound molecule found in blood only on
erythrocytes; thus, whole blood samples, not serum or plasma, are required for accurate
determination of AChE activity in blood. Another concern with the Dalhousie measurements is
that AChE levels should always be compared to the established reference values of the clinical
laboratory in which the measurements are performed, rather than to the values of a specific and
limited set of experimental controls, because laboratory reference values are generally based on
many more samples and reflect a more realistic range of normal activities. The Dalhousie study
relied instead on experimental controls. A second reason is that the number of Canadian
personnel with detectable levels of temephos or 3-PBA was much smaller than the number of
individuals with symptoms. A third reason is that Canadian personnel were not sampled at the
time of initial signs and symptoms.
Absent data regarding the concentration of OPs or pyrethroids in relevant environmental
samples collected proximal to the onset of symptoms or in samples from affected U.S. Embassy
personnel at the time of initial signs and symptoms, it is not possible to determine whether
exposures were at levels that might reasonably cause toxic effects, particularly in vulnerable
individuals. This issue is complicated by the fact that there is growing evidence that at least some
of the neurotoxic effects of OPs are mediated by mechanism(s) other than or in addition to AChE
inhibition (Anger et al., 2020; Costa, 2006; Naughton and Terry, 2018; Pope, 1999).
With regards to the overlap of symptoms between chemical exposures and the Havana
cases, epidemiologic and clinical studies have linked occupational or environmental chemical
(including OP and pyrethroid insecticide) exposures to a subset of the distinctive early phase
symptoms and many of the nonspecific chronic problems suffered by some of the U.S. Embassy
Havana cases (see Appendix D).
Acute OP poisoning manifests as a clinical toxic syndrome known as cholinergic crisis,
which includes parasympathomimetic symptoms (sweating, tears, rhinorrhea, salivation,
urination, diarrhea, increased bronchial secretions and bronchoconstriction, and bradycardia),
muscle fasciculation followed by flaccid paralysis, loss of consciousness and seizures (Eddleston
et al., 2008; Hulse et al., 2014). Subacute and chronic OP exposures involving doses that do not
cause significant AChE inhibition, do not cause cholinergic signs but can be associated with
neurotoxic effects not only in individuals with occupational exposures, but also in the general
public. OP-associated neurotoxic effects, which may or may not be associated with AChE
inhibition in affected individuals, include hearing loss, tinnitus, dizziness, headache, fatigue,
motor incoordination, nausea, insomnia, anxiety, memory deficits and inability to concentrate
(Anger et al., 2020; Ashok Murthy and Visweswara Reddy, 2014; Choochouy et al., 2019;
Crawford et al., 2008; Dassanayake et al., 2007, 2008, 2009; Dundar et al., 2016; Edwards and
Tchounwou, 2005; London et al., 1998; Richter et al., 1992; Roldan-Tapia et al., 2006; Ross et
al., 2013; Teixeira et al., 2002). Some of these effects were reported among affected DOS
employees stationed in Havana.
There are significantly less epidemiologic and clinical data available regarding the
neurotoxic effects of pyrethroids than there are for OPs, but published studies report associations
between acute, subacute, and chronic pyrethroid exposures and hearing loss, visual disturbance,
tinnitus, dizziness, headache, nausea, fatigue, and deficits in memory and concentration in
occupational cohorts and in the general public (Campos et al., 2016; Chen et al., 1991;
Lessenger, 1992; Müller-Mohnssen, 1999; Richardson et al., 2019; Teixeira et al., 2002; Xu et
al., 2020; Zeigelboim et al., 2019). High dose acute pyrethroid exposures are also associated with
tremors and seizures (Bal-Price et al., 2015).
In summary, the committee concludes that it is not likely that acute high-level exposure
to OPs and/or pyrethroids contributed to the unexplained illnesses observed in the Havana cases
because there is no convincing evidence of acute high-level exposures and the clinical history of
affected U.S. Embassy personnel is not consistent with acute OP poisoning. It is also unlikely
that subacute or chronic OP or pyrethroid exposures precipitated the onset of the distinctive acute
symptoms associated with the Havana cases. However, given experimental data indicating that
interactions between pesticides (particularly OPs) and psychosocial or physical stressors, the
latter including noise and non-ionizing radiation, can increase risk and/or severity of adverse
outcomes, the committee could not rule out the possibility, although slight, that exposure to
insecticides, particularly OPs, increased susceptibility to the triggering factor(s) that caused the
Embassy personnel cases. Alternatively, differential exposure to insecticides amongst affected
individuals may have contributed to the clinical heterogeneity of the acute symptoms noted in
Havana cases, since OP and pyrethroid exposures are associated with a subset of these acute
symptoms (see Appendix D). The committee also finds it plausible that subacute or chronic OP
and/or pyrethroid exposures contributed to the nonspecific chronic symptoms observed in
affected U.S. Embassy personnel.