Developmental Neurotoxicity

Prevalence

According to Grandjean and Landrigan: “Disorders of neurobehavioural development affect 10–15% of all births, and prevalence rates of autism spectrum disorder and attention-deficit hyperactivity disorder seem to be increasing worldwide. Subclinical decrements in brain function are even more common than these neurobehavioural developmental disorders. All these disabilities can have severe consequences —they diminish quality of life, reduce academic achievement, and disturb behaviour, with profound consequences for the welfare and productivity of entire societies.”
Reference: 2014. Neurobehavioural effects of developmental toxicity. Lancet Neurology 13:330–38

In 2014, Fluoride was identified as one of 11 Developmental Neurotoxicants

The importance of considering other indices of fluoride neurotoxicity besides reduced IQ was discussed by a team of Mexican researchers. (Rocha-Amador 2009). As the researchers noted:

“Intuitively, though it might seem that an IQ test would be an ideal measure [for determining the neurotoxic effects of a chemical], this assumption would be ill founded, because some toxicants could affect only specific functions, such as attention, memory, language, or visuospatial abilities without clear decrements on IQ scores. Furthermore, the exposure dose as well as mixtures of toxicants are important factors that also need to be considered.”

To help highlight this point, the researchers cited their earlier study which found that although fluoride did not affect overall IQ scores, it did affect reaction time and visual-spatial organization. (Calderon 2000).

To better understand fluoride’s non-IQ effects on the brain, the Mexican team suggests using the Rey-Osterrieth Complex Figure (ROCF) Test:

“[I]t is imperative to have a tool for rapid risk assessment to quantitatively measure health effects. In neuropsychology there are several tests that can be used for this purpose but many of them have issues including lack of validation and standardized values for the Mexican population, furthermore the influence of cultural factors also limits their usefulness. These issues could be solved in part by the Rey-Osterrieth Complex Figure (ROCF) Test. This test is one of the most widely used in neuropsychology for the evaluation of visuospatial constructional ability and non-verbal memory skills in both clinical and research settings.”
SOURCE: Rocha-Amador, D. et al  (2009). Use of the Rey-Osterrieth Complex Figure Test for neurotoxicity evaluation of mixtures in children. Neurotoxicology 30(6):1149-54

The following studies used various tests to determine fluoride’s neurobehavioral effects, including the ROCF test.

Human Studies on Fluoride’s Neurobehavioral effects:

“In this cross-sectional study, the psychomotor performance and memory skills of a fluoride-exposed group (FEG) of 64 male workers in an aluminum potroom were compared with those of 60 male workers in a nonfluoride-exposed group (NFEG). The FEG had a mean age of 37.59±4.82 yr and had been employed for 13.06±4.29 yr, which compared closely with the NFEG. Both groups were selected randomly and had no previous history of neuropsychological, hepatic, renal, or immune disorders. The neurobehavioural functions were measured using the World Health Organization neurobehavioural core test battery (NCTB), a computer based test, for reaction time, and a Purdue pegboard test for manual dexterity and hand-eye coordination. The FEG had significant impairments compared to the NFEG for mean reaction time, Purdue pegboard for the preferred hand and both hands, pursuit aiming, digit span, Benton Visual Retention (p<0.001), and digit symbol memory (p<0.01). The digit symbol performance scores, but not those for the other parameters, decreased with increased work duration (p<0.05). Overall, the mechanism for the impairments did not appear to be the result of impaired thyroid function. We conclude that neurobehavioural testing is useful for detecting impairment of psychomotor performance and memory that associated with occupational F exposure.”
SOURCE: Yazdi SM, et al. (2011). Effects of fluoride on psychomotor performance and memory of aluminum potroom workers. Fluoride 44:158-62.

“The objective of this study was to explore the potential usefulness of the ROCF [Rey-Osterrieth Complex Figure] test as a tool for a rapid assessment to evaluate visuospatial organization (Copy) and visual memory (Immediate Recall) in children living in areas of Mexico exposed to different mixtures of neurotoxic agents including [fluoride], [arsenic], [lead], DDT or PCBs.” RESULTS: “This study provides evidence that children living in high risk areas were exposed to either fluoride, arsenic, lead, DDT or PCBs and these contaminants could contribute, to some degree, to children’s low performance observed in the tests of the Rey-Osterrieth Complex Figure. The highest proportion of children (89%) with Copy performance below – 1 SD was observed in children from fluoride–arsenic area. Approximately 9 out of 10 children were unable to copy the ROCF as expected for their age. For example, the expected score on Copy for a 6-year-old child is 9.94 +- 2.28 points. A child classified in the category below -1 SD means that his score was lower than 7.66. In the fluoride–arsenic area children had z-scores as low as -5 SD (scoring only two points on the test). For Immediate Recall, the proportion of children in the lowest category was 59% and almost 6 out of 10 children were unable to draw the figure as expected for their age after 3 min had elapsed. Following the same example of a 6-year-old child, the expected value for drawing the figure from memory is 7.26 +- 2.45. One child classified in the – 1 SD category had a score below 4.81 points. Fluoride correlated inversely with Copy and Immediate Recall r = _0.29 and r = _0.27 (adjusted values). Previous data have reported a similar association between Copy scores and [urinary fluoride] in children.”
SOURCE: Rocha-Amador D, et al. (2009). Use of the Rey-Osterrieth Complex Figure Test for neurotoxicity evaluation of mixtures in children. Neurotoxicology 30(6):1149-54.

“There are numerous reports of mental and physiological changes after exposure to fluoride from various routes (air, food, and water) and for various time periods (Waldbott et al. 1978). A number of the reports are, in fact, experimental studies of one or more individuals who underwent withdrawal from their source of fluoride exposure and subsequent re-exposures under “blind” conditions. In most cases, the symptoms disappeared with the elimination of exposure to fluoride and returned when exposure was reinstated. In some instances, when the fluoride was given in water, this procedure was repeated several times under conditions in which neither the patient nor the provider of the fluoride knew whether the water contained fluoride. Also reported are instances when fluoride-produced symptoms occurred when people moved into a community with fluoridated water but disappeared when the individuals moved to a nonfluoridated community. Spittle (1994) reviewed surveys and case reports of individuals exposed occupationally or therapeutically to fluoride and concluded there was suggestive evidence that fluoride could be associated with cerebral impairment. A synopsis of 12 case reports of fluoride-exposed people of all ages showed common sequelae of lethargy, weakness, and impaired ability to concentrate regardless of the route of exposure. In half the cases, memory problems were also reported.”
SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. National Academies Press, Washington D.C. p. 208-09.

“The effects of excessive fluoride intake during pregnancy on neonatal neurobehavioral development and the neurodevelopment toxicity of fluoride were evaluated. Ninety-one normal neonates delivered at the department of obstetrics and gynecology in five hospitals of Zhaozhou County, Heilongjiang Province, China were randomly selected from December 2002 to January 2003. The subjects were divided into two groups (high fluoride and control) based on the fluoride content in the drinking water of the pregnant women. . . . There were significant differences in the neonatal behavioral neurological assessment score and neonatal behavioral score between the subjects in the endemic fluoride areas and the control group. . . . [N]eurobehavioural capability and agonistic muscle tension from the high fluoride group were impaired, resulting in a statistically significant lower overall (total) assessment score than in the control group (p<0.05). . . . [V]arious neurobehavioral capabilities, such as non-biological visual, biological visual, and auditory directional reactions of the neonates from the high fluoride group lagged behind those of the control group with differences that are statistically significant (p<0.05). . . . NBNA examination can help to detect mild damage to brain functions. The results of the examination indicate that high fluoride levels can cause adverse effects in the neurobehavioral development of neonates. . . . The present observations indicate that fluoride, as a toxic material to nerve development, can have an adverse impact on the neurobehavioral development of neonates and can cause abnormal changes of neurobehavioral capability during the neonate period with a negative impact on the future development of both the body and intelligence of the neonate. Therefore, in endemic fluoride areas, great effort should be made to reduce fluoride level in the water.”
SOURCE: Li J, Yao L, Shao Q-L. (2004). Effects of high-fluoride on neonatal neurobehavioural development. Chinese Journal of Endemiology 23:464-465. (Republished in Fluoride 2008; 41:165-70).

“In recent years, the damage fluoride inflicts on nonskeletal organs, and in particular the nervous system, has received a great deal of attention. However, research on the effects of fluoride on neurobehavioral function (as measured by the neurobehavioral core test battery, or NCTB) is new to the literature. By relating NCTB to fluoride exposure, the purpose of this study was to investigate the effects of occupational fluoride exposure on the central nervous system and to determine to what extent the level of exposure correlates with those effects and hopefully thereby provide early warning indicators that can be used to protect the health of workers who have occupational contact with fluoride. RESULTS: The results of the NCTB testing in this investigation revealed significant differences among the fluoride-exposed groups for various indices as compared to reference standards and the controls, with particular deficits in attention, auditory retention, and physical dexterity and acuity as well as abnormal emotional states. These findings are consistent with the symptoms of endemic fluoride poisoning, suggesting occupational exposure to fluoride has harmful effects on the higher functions of the central nervous system, negatively influencing both cognitive and autonomic functioning. There is a definite relationship between the damage caused by fluoride and the level of exposure.”
SOURCE: Guo Z, et al. (2001). Study on neurobehavioral function of workers occupationally exposed to fluoride. Industrial Health and Occupational Disease 27:346-348. (Republished in Fluoride 2008; 41:152-55).

“After controlling by significant confounders, urinary fluoride correlated positively with reaction time and inversely with the scores in visuospatial organization. IQ scores were not influenced by fluoride exposure. An increase in reaction time could affect the attention process, also the low scores in visuospatial organization could be affecting the reading and writing abilities in these children.”
SOURCE: Calderon J, et al. (2000). Influence of fluoride exposure on reaction time and visuospatial organization in children. Epidemiology 11(4): S153.

“This study assessed the health effects associated with occupational exposure to methyl bromide and sulfuryl fluoride among structural fumigation workers. . . . Sulfuryl fluoride exposure over the year preceding examination was associated with significantly reduced performance on the Pattern Memory Test and on olfactory testing. . . .  Conclusions: Occupational sulfuryl fluoride exposures may be associated with subclinical effects on the central nervous system, including effects on olfactory and some cognitive functions.”
SOURCE: Calvert GM, et al. (1998). Health effects associated with sulfuryl fluoride and methyl bromide exposure among structural fumigation workers. Am J Public Health. 88(12):1774-80.

“Neurobehavioral functions affected by methyl bromide exposure were evaluated in California structural and soil fumigators using methyl bromide and sulfuryl fluoride. . . . The greater number of symptoms and reduced performance on all cognitive tests in sulfuryl fluoride fumigators compared to the Reference Group plus the absence of published research on this compound suggest that the data base for sulfuryl fluoride is inadequate.”
SOURCE: Anger WK, et al. (1986). Neurobehavioral evaluation of soil and structural fumigators using methyl bromide and sulfuryl fluoride. Neurotoxicology. 7(3):137-56.

“Two experiments were conducted in order to determine if challenge testing, a procedure developed by clinical allergists, could be used to provoke behavioral reactions to chemicals found in municipal waters. In one experiment, 10 male and 32 female volunteers tracked a moving target and monitored lights after receiving sublingual drops that contained only water or varying amounts of sodium fluoride and nitrate. Dosage levels in this experiment equaled, exceeded, of fell below those found in municipal waters. In a second experiment, 20 females performed this task after receiving sublingual drops of the same test substances in a repeated measures design; dosage levels equaled or exceeded levels found in municipal waters by 100 or 500 times.  Neither type nor amount of chemical affected primary task performance; however, after receiving sublingual drops in the first (between-subjects) experiment, subjects paid less attention to lights on their right. In the second experiment, subjects made more errors and had longer response latencies after they received moderate and very high concentrations of the test substances. It was concluded that challenge testing is a safe but effective technique for provoking and studying reactions to chemicals when it is combined with a sensitive measure of sensorimotor performance.”
SOURCE: Rotton J, et al. (1983). Behavioral Effects of Chemicals in Drinking Water. Journal of Applied Psychology 67:230-38.

“Clinical evidence suggests that uranium hexafluoride may have a rather marked central nervous system effect…. It seems most likely that the F [code for fluoride] component rather than the T [code for uranium] is the causative factor. . . . Since work with these compounds is essential, it will be necessary to know in advance what mental effects may occur after exposure…This is important not only to protect a given individual, but also to prevent a confused workman from injuring others by improperly performing his duties.”
SOURCE: Letter to Col. Stafford L. Warren from John L. Ferry, Assistant Captain, U.S. Medical Corps. (April 19, 1944). Request for Animal Experimentation to Determine Central Nervous System Effects.

animal STUDIES ON FLUORIDE’S NEUROBEHAVIORAL EFFECTS – SEE ALSO

“The results of the present study indicate that perinatal exposure to sodium fluoride (NaF), at dose levels below those associated with gross malformations and/or overt neurotoxic effects, produces both short and long term sex and dose specific neurobehavioural alterations in rat offspring.”
SOURCE: Bera I, et al. (2007). Neurofunctional effects of developmental sodium fluoride exposure in rats. European Review for Medical and Pharmacological Sciences 11(4):211-24.

“Administration of sodium fluoride with drinking water produced both behavioural and dental toxicities and not lethality in the present study. A suppression of spontaneous motor activity, a shortening of rota-rod endurance time, a decreased body weight gain and food intake, a suppression of total cholinesterase and acetylcholinesterase activities and dental lesion were observed in test animals.”
SOURCE: Ekambaram P, Paul V. (2001). Calcium preventing locomotor behavioral and dental toxicities of fluoride by decreasing serum fluoride level in rats. Environmental Toxicology and Pharmacology 9(4):141-146.

“Sodium fluoride treatment suppressed spontaneous motor activity. But no change was observed in the motor coordination of these animals. A suppression of spontaneous motor activity suggests that fluoride has, by a central action, inhibited motivation of these animals to exhibit locomotor behavior.”
SOURCE: Paul V, et al. (1998). Effects of sodium fluoride on locomotor behavior and a few biochemical parameters in rats. Environmental Toxicology and Pharmacology 6: 187–191.

“This study demonstrates a link between certain fluoride exposures and behavioral disruption in the rat. The effect on behavior varied with the timing of exposure during CNS development. Behavioral changes common to weanling and adult exposures were different from those after prenatal exposures… Experience with other developmental neurotoxicants prompts expectations that changes in behavioral function will be comparable across species, especially humans and rats… [A] generic behavioral pattern disruption as found in this rat study can be indicative of a potential for motor dysfunction, IQ deficits and/or learning disabilities in humans.”
SOURCE: Mullenix P, et al. (1995). Neurotoxicity of Sodium Fluoride in Rats. Neurotoxicology and Teratology 17:169-177.

“In this experiment, the freeze response to auditory stimuli in the pups showed significant delay, indicating that relatively high doses of fluoride can negatively influence the development of auditory nerves. Guan Zhizhong et al[8] report that the offspring of rats exposed to fluoride have retarded cerebral development and exhibit changes in neural cell ultrastructure. The results of the present experiment suggest that the effects of high doses of fluoride on the behavior development of the offspring are visible primarily as slight delays in response times, particularly with regard to motor and coordination function and well as muscle strength. The measurement of the thickness of the cerebral cortex of offspring on day 21 revealed that the 25 mg/L group had a significantly thinner cerebral cortex as compared to the control; this histological analysis indicates that fluoride slows the growth of brain cells.”
SOURCE: Wu N, et al. (1995). Research on the abnormal behavior of rats exposed to fluoride. Chinese Journal of Control of Endemic Diseases 14(5):271.

“When rats were treated 6 hr a day for 5 mo. with HF concentrations of 3, 1, 0.5, and 0.1 mg/m-3, it caused functional changes in the CNS, as shown by the condition reflex method and the measurement of chronaxy. There was inhibition of the blood alkaline phosphatase activity and pathomorphological changes in the CNS, bone and tooth tissues and internal organs. The extent of the changes depended on the concentration of HF. The maximum allowable concentration of HF for the air at working places presently accepted, 0.5 mg/m-3, is too high.”
SOURCE: Vishnevskii VL, El Nichnykh LN. (1969). (A toxicological and morphological characterization of the action of different concentrations of inhaled hydrogen fluoride on the body.). Tr Tsentr Nauchno-Issled Proektn-Konstr In. 2: 143-147.

“General malaise, asthenia, and apathy developed to a marked degree in the monkeys exposed to the BeF2 (beryllium fluoride) aerosol, and in those under the heaviest BeHPO4 exposure. The monkeys retreated to the furthest corner of their cages and paid no attention to light flashed at them. They remained in this withdrawn and listless condition until death. Monkeys which inhaled the BeSO4 aerosol faired best of all.”
SOURCE: Schepers GWH. (1964). Biological action of beryllium: Reaction of the monkey to inhaled aerosols. Industrial Medicine and Surgery 33: 1-16.