FQT/FQAD mimics many other conditions, and Lead Toxicity is one of them. Over the years, many victims have noticed this observation. The older a person is, the greater the exposure to Lead in their younger years, and the greater the chance that Acute Intermittent Lead Toxicity could be occurring in later years under certain conditions. Older women, such as myself, are one of the groups at increased risk. Here, I provide possible mechanisms that may relate Lead Toxicity secondary to Fluoroquinolone Toxicity. To the extent that other heavy metals and toxins are stored in bones and teeth (arsenic, cadmium, aluminum, mercury, and fluorine being the most well known ones), similar mechanisms of toxicity may apply.
It’s probably best to start off reading the article I wrote for another website: Love May Be Fleeting, but Lead Is Forever: Testing for Lead Toxicity. This summarizes why I think chronic and potentially acute episodes of Lead Toxicity may be an ongoing issue for me, and possibly others as well. It’s written for a general audience, so it’s not too “science heavy” for those without a science or medical background. There is also a list of Lead-related references provided at the end of the article.
A more detailed mechanism to get through is the potential relationship of FQs to an enzyme called “V-ATPase”. The short cut version is that V-ATPase is an enzyme involved in bone breakdown, to help release the calcium and phosphorus stored in our bones into our blood. This will occur when we are low on calcium or phosphorus. When might we be low on calcium and other minerals? Possibly after taking an FQ, which is known to “bind up” or “chelate” calcium and other minerals from our cells. So V-ATPase activity will increase, releasing any stored Lead in our bones back into our blood. Unfortunately, there’s an additional possibility that FQs also “bind up” or “inhibit” the enzyme V-ATPase as well while on the drug. In this case, when our bodies need calcium and phosphorus the most, we’re unable to get it from our bones while we’re still taking the FQ. After we stop the FQ, the V-ATPase inhibition ends. At that point in time, there will be a “rebound effect” of V-ATPase to restore calcium and phosphorus to our cells. This “rebound effect” could be dramatic in those of us with FQT/FQAD, resulting in the delayed symptoms of tendon ruptures as well as all the other symptoms of FQT/FQAD. Again, during breakdown of bone secondary to increased V-ATPase activity, Lead stored in our bones is released as well. This could potentially result in acute Lead Toxicity for those of us with high levels of Lead stored in bone. Although it can seem like a tough read, I would encourage people to read about this mechanism in Additional Targets of Fluoroquinolone Antibiotics (Part 1) Scroll down about 60% of the Page to V-ATPases (vacuolar H+-ATPase): Target for Osteoporosis /Adverse Effects. Although it initially looks like a difficult read, if you keep reading, I go through my own case as an example of how this mechanism might have come into play with my own case of FQT/FQAD.
With both Hyperthyroidism and Hyperparathyroidism, increased rates of bone breakdown occur, releasing any stored Lead from our bones into our bloodstream as well. This is why if a person has Hyperthyroidism or Hyperparathyroidism, and they have higher amounts of stored Lead in their bones from their younger years, they are at possible risk for Acute Lead Toxicity during these times (see case study references below). Because Lead Toxicity is a possibility with Hyperthyroidism and Hyperparathyroidism patients, understanding how to test for it, or at least to suggest it to your physicians as a possibility, is probably a good idea. No, there aren’t many documented cases in the literature. But how many physicians even remotely think to test for it? If a person has frank Hyperthyroidism or Hyperparathyroidism, testing for Blood Lead levels and additional tests for Lead toxicity such as FEP/ZPP (see reference below) would probably be a good idea as well. The older a person is, the greater the risk for acute outbreaks of Lead Toxicity. Post menopausal women, or women with osteoporosis might be at greater risk for chronically increased blood levels of Lead also. Lead Toxicity can also look like Acute Intermittent Porphyria, another condition that many FQT/FQAD victims have considered (and some have tested positive for) over the years. Here are the links to Thyroid and Parathyroid Related Testing, and Testing On Your Own — When the Docs Refuse if you decide to go that route.
Fluoride Toxicity and Mercury Toxicity (as well as Lead and other heavy metal toxicities) are covered extensively on the internet, which is why I don’t cover it in more detail on this website. However, over the years, it’s been noted that symptoms of FQT/FQAD resemble these toxicities, and some people have even tested high for heavy metals post FQ reaction. Research confirms FQs not only chelate important essential minerals, but also affects the enzyme V-ATPase which works to help replace those minerals when we are low. Understanding how FQs can contribute to release of toxic substances stored in bone (and in teeth, for those victims who experience severe tooth wear, “crumbling” of teeth, and tooth loss) will hopefully lead to more systematic monitoring for these toxicities overall within the FQT/FQAD population.
Studies which would be interesting to do on the FQT/FQAD population would include using K-XRF (see references below) and blood Lead testing to help answer the question if FQ-Affected have a greater lifetime Lead burden than those not affected by FQs, and if so, is that showing up in blood Lead levels during the acute phase (first six months) or during relapses. In my own case, I also appear to have several rare genetic variants in the V-ATPase enzyme, most notably clustered in the exact area where the FQs have been confirmed to bind and interact, as well as in some of the regulatory areas of the enzyme. So I think looking at the genetic aspects of this enzyme within the FQT/FQAD population would also be worthwhile.
Some additional relevant references about Lead Toxicity and other heavy metal toxicities are provided below.
Agency for Toxic Substances and Disease Registry: Lead CE for physicians: A good source for information regarding Lead in general; this page shows the biological fate of Lead in our bodies.
Lead poisoning secondary to hyperthyroidism: report of two cases “Factors that affect calcium distribution also affect lead distribution. For example, high phosphate intake favours storage in bone, and vitamin D promotes deposition of lead in bones. Parathyroid hormone and dihydrotachysterol mobilise the lead in bones, leading to greater concentrations in blood (10). High alkaline phosphatase concentrations reflect the increase in bone turnover. Several conditions known to increase bone turnover, such as pregnancy (12–14), chemotherapy (15–17), tumorous infiltration of bone (18), or postmenopausal osteoporosis (19), may be associated with the mobilisation of lead in bone stores, leading to chronic lead poisoning. Hyperthyroidism is known to increase bone remodelling (20–22). Therefore, hyperthyroidism may also result in lead poisoning . . . Our two case reports highlight two phenomena. An increase in bone turnover secondary to hyperthyroidism may lead to the liberation of lead stores from bone into the blood stream and, furthermore, such lead poisoning may develop even when there has been no lead ‘administration’ for several years, as observed in patient 2, because the lead stored in bone may be mobilised over a period of years. These two cases demonstrate that a metabolic disease involving a high rate of bone remodelling is able to generate clinical symptoms of lead poisoning. Lead poisoning is a major environmental health problem and physicians must be aware of the endocrine disorders, such as hyperthyroidism and hyperparathyroidism, that lead to increased bone turnover and possible lead mobilisation. Atypical symptoms should draw the physician’s attention to the possibility of lead poisoning, particularly in workers with occupational exposure to lead or in areas where lead poisoning is endemic.
Understanding Blood Testing Results for Adult Exposure to Lead “There are several methods to identify and measure lead in human tissue or fluids. The most useful and common method is to measure the amount of lead in whole blood. A blood lead test is mainly an estimate of recent exposure to lead, but it is also in equilibrium with bone lead stores. The blood lead level (BLL) alone is not a reliable indicator of prior or cumulative dose or total body burden. When interpreting the BLL, key questions are whether the exposure has been 1) of short-term or long-term in duration; 2) recent or in the past; and 3) in large or small amounts. . . . There are two tests available to measure intermittent lead exposures over time, the erythrocyte protoporphyrin (EP), which can be measured as free EP (FEP) or zinc protoporphyrin (ZPP). These tests measure biological effect and are an indirect reflection of lead exposure. Following lead absorption, one of the physiological changes that occur in the body is a buildup of protoporphyrin in red blood cells. This physiological change can be accurately measured with an FEP or a ZPP test. Increases in FEP or ZPP are not detectable until BLLs reach 25μg/dL. An increase in FEP or ZPP usually lags behind an increase in BLL by two to six weeks. Elevated BLL and Normal FEP/ZPP = Recent exposure 2-6 weeks. Elevated BLL and Elevated FEP/ZPP = Chronic/ongoing exposure. Although some diseases and iron deficiency anemia can elevate FEP or ZPP, lead absorption is the most likely cause for such an increase in healthy working individuals. Further, the FEP or ZPP levels increase abruptly when blood lead levels reach about 40 μg/dL, and they tend to stay elevated for 3-4 months (the average life span of a red blood cell).”
Lead Poisoning Mimicking Acute Porphyria! “Excess porphyrins in the urine, has been noted in cases of lead poisoning as far back as 1895. Several studies on the effects of lead have revealed inhibition at several sites of heam biosynthesis . This is consistent with our findings. The most common means of exposure are inhalation of air contaminated with lead dust, ingestion of lead -tainted food or water, or direct contact with lead -polluted soil.”
Depressed Excretion of 6²-Hydroxycortisol in Lead-Toxic Children “6β-Hydroxycortisol (6βOHF) is a highly polar metabolite of cortisol, probably formed in the endoplasmic reticulum of hepatocytes by cytochrome P-450-dependent microsomal monoxygenases. Lead decreases the activity of cytochrome P-450-dependent microsomal hydroxylases in vivo and in vitro . . . These findings suggest that lead, at relatively low concentrations, may interfere with hepatic microsomal formation of a cortisol metabolite.”
Lead Poisoning From Mobilization of Bone Stores During Thyrotoxicosis. “We describe a case of thyrotoxicosis accompanied by markedly elevated blood lead levels (initially 53 µg/dl) in a 37-year-old woman. No current source of lead exposure was found; the woman gave a history indicative of lead exposure as a child and as an adult 7 years previously, however. In addition, she was found to have markedly elevated bone lead levels, as measured by K-x-ray fluorescence (154±5 in the mid-tibia and 253 ±6 µg/g bone mineral in the patella), and an increased serum osteocalcin level (2.76 nmol/l), reflecting the increased bone turnover that often accompanies hyperthyroidism. During treatment with propylthiouracil, serial observations demonstrated a decline in serum osteocalcin that paralleled a decline in blood lead levels. Bone lead levels did not change appreciably. The patient also continued to have lingering neuropsychological symptoms consistent with chronic lead effects. We suggest that increased bone turnover accompanying thyrotoxicosis led to clinically significant lead poisoning in this patient, due to mobilization of accumulated bone lead stores acquired many years earlier. This phenomenon raises the general issue of more subtle forms of lead exposure from increased bone turnover states (e.g., osteoporosis). . . . A 37-year-old woman employed as a salesperson in a clothing store experienced persistent fatigue, insomnia, difficult concentrating, abdominal cramps, weight loss, muscle and joint aching, and tremor for several months. After reading newspaper reports on lead poisoning, she wondered if her symptoms might be related to work she last performed 7 years earlier, when she removed paint during the course of renovating houses. She requested a blood lead tests from an otolaryngologist who was treating her for an ear infection. The physician found that her chemistry screen (glucose, liver function tests, blood urea nitrogen, creatinine, calcium, and phosphorus) was normal, but that she had an elevated blood lead level of 2.46 µmol/l (51 µg/dl) and an elevated erythrocyte protoporphyrin (EP) level of 0.78 µmol/l (44 µg/dl; normal <0.62 µmol/l or 35 µg/dl) . . . This case is important because it demonstrates lead poisoning in the absence of an ongoing source of external lead exposure in a hyperthyroid patient, detects elevated bone lead stores through K-X-ray fluorescence, demonstrates increased bone turnover through elevated serum osteocalcin levels, and documents a decline in blood lead without the use of chelating agents as hyperthyroidism and bone turnover come under control. This patient’s bone lead levels were very high. Her history suggests that they probably derived from remote childhood exposures and 6 months of adult exposure as a lead paint remover. However, her tibia lead levels are comparable to those seen among male workers with several decades of lead exposure [El-Sharkawi et al., 1986; Hu et al., 1991]. This raises the possibility that the patient’s lead exposure occurred when she was undergoing rapid bone deposition (e.g., the skeletal growth of adolescence), thereby leading to unusually high bone lead levels. Clarification of this issue will await additional studies of bone lead and exposure . . . A case has previously been described of lead poisoning in a young patient who had a retained bullet in his leg for over 3 years [Cagin et al., 1978]. Upon developing hyperthyroidism, he was found to have a blood lead level >100 µg/dl. Bone lead content measured by chemical analysis of a bone biopsy sample was 207 µg/g (wet bone, presumably). This level decreased as his hyperthyroidism and lead poisoning were treated with propylthiouracil and chelating agents. Significantly increased blood lead levels have been noted in epidemiological studies of postmenopausal women [Silbergeld et al., 1988]. Given the size of her lead burden, the patient in this case may be at risk for lead intoxication again when she enters the postmenopausal period, possibly exacerbated by l-thyroxine therapy. This case also raises the issue of long-term health effects associated with lead poisoning. The deficits seen in this patient’s test performance were determined to be longstanding because the visuospatial deficits seen occurred across tasks (not just on complex constructional tests such as Block Designs, which might be seen in adult lead exposure) [White et al., 1990] and because the patient’s performance on arithmetic knowledge closely paralleled that seen on visuospatial tasks, a correlation often seen developmentally [Rourke, 1985]. In addition, the identification of manual motor and cognitive abnormalities despite normalization of thyroid status is consistent with a longstanding rather than acute process . . . Finally, this case demonstrates the clinical utility of a K-XRF instrument for the in vivo measurement of bone lead stores when one suspects a significant internal source of lead exposure . . . X-ray fluorescence was critical in establishing very high bone stores suggestive of childhood lead poisoning. In a study of adults with medical documentation of hospitalization for childhood lead poisoning, 37% were unaware of this history [Hu, 1991]. Given the toxic potential of bone lead stores demonstrated by this case study, the continued lowering of the amount of lead exposure that has been associated with significant health effects in recent research, and the continued widespread nature of lead exposure in the U.S. [ATSDR, 1988], some combination of K-XRF and blood lead testing may eventually become an important screening procedure for select populations of individuals such as patients with thyroid disorders, women contemplating pregnancy, and patients with clinical syndromes suggestive of a low-level lead effect.”
Lead and osteoporosis: mobilization of lead from bone in postmenopausal women. “Although it has been known that humans accumulate lead in bone, mineralized tissue has been considered primarily as a sequestering compartment and not as a site of toxic action for lead. However, experimental data indicate that bone lead can be released during conditions of demineralization, such as pregnancy and lactation. We have examined lead status in women, before and after menopause, using the NHANES II dataset compiled between 1976 and 1980. In 2981 black and white women there was a highly significant increase in both whole blood and calculated plasma lead concentration after menopause. The results indicate that bone lead is not an inert storage site for absorbed lead. Moreover, lead may interact with other factors in the course of postmenopausal osteoporosis, to aggravate the course of the disease, since lead is known to inhibit activation of vitamin D, uptake of dietary calcium, and several regulatory aspects of bone cell function. The consequences of this mobilization may also be of importance in assessing the risks of maternal lead exposure to fetal and infant health.”
Lead as a Risk Factor for Osteoporosis in Post-menopausal Women “Lead exposure is increasingly becoming an important risk factor for osteoporosis . . . Postmenopausal women are at a higher risk for bone lead release because of hormonal and age related changes in bone metabolism. Estrogen deficiency is associated with increase in osteoclasts number and activity leading to both the early and late form of osteoporosis.”
Osteoporosis, lead, and baby boomers: When time gets the lead out. “By the time the boomers’ skeletons were at their maximum mineral density (early adulthood), they had had ample opportunities to absorb and retain lead in their bones. Absorption of lead through inhalation might have occurred through exposure to automotive exhaust, or by handling gasoline in the course of fueling vehicles or doing household chores. Lead could have been ingested by drinking water from lead-soldered plumbing, or eating foods from lead soldered cans. Exposures to lead from paint could have happened in several ways. One is handling or being exposed to lead -based paints removed from or applied to homes, schools, and other buildings during renovations. Children could have absorbed lead through either inhalation of fumes and dusts, or through deliberate or inadvertent ingestion of lead paint chips, fragments, and dusts . . . At any stage of life, bone mass loss can occur if conditions warrant it: Endocrine, liver, and kidney disease can cause bone loss, as can certain cancers and some metabolic disorders. Long-term use of steroids like prednisone can cause bone loss, as can heparin, and some anti-epilepsy drugs. Alcohol use can contribute to osteoporosis, as can dietary deficiencies due to alcoholism. Nutritional deficiencies arising from insufficient food intake, eating disorders, ‘fad’ weight loss diets, and medical conditions that interfere with food intake can all promote bone loss. Immobilization from illness or injury causes bone to lose density. Astronauts have experienced bone thinning due to weightlessness. Some bone loss is related to the passage of time, and it starts long before the familiar “old age” signs are present: After age 40, both men and women lose about 5% to 10% of their bone mass each decade. In women after menopause different stages of life, and for a variety of reasons. For instance: [not undergoing estrogen replacement therapy], bone mass loss speeds up five to seven fold until about age 70, when the rate of bone loss returns to the premenopausal 5% to 10% rate per decade.”
Lead induced thyroid dysfunction in Wistar albino rats and its amelioration with Ocimum sanctum leaf extract – a hormonal and histopathological study. “Results in the present study revealed that lead acetate caused a dose dependant reduction in T3, T4 and TSH levels when compared to control. Hisopathologically thyroid shows hemorrhages and sever desquamation of epithelial cells, complete absence of acinar colloid in majority of acini, disruption of acini, atrophy of acini and interacinar fibrous tissue proliferation in majority of the animals.”
Lead exposure causes thyroid abnormalities in diabetic rats. “Treatment of diabetic animals with lead acetate resulted in significant weight loss (P < 0.001). It also caused an increase in thyroid stimulating hormone levels (P < 0.05) and reductions in thyroxine (P < 0.05) and triiodothyronine levels (P < 0.01), a clinical picture consistent with hypothyroidism.”
Bone lead as a new biologic marker of lead dose: recent findings and implications for public health. “Measurements of lead in bone have recently become the focus of research because a) bone lead levels serve as a cumulative dosimeter of lead exposure over many years (because of lead’s long residence time in bone), and cumulative exposure may be more predictive of chronic toxicity than recent exposure, which is what blood lead levels mostly reflect; b) there is suspicion that heightened bone turnover (e.g. during pregnancy, lactation, and aging) may liberate enough stored lead to pose a significant threat of delayed toxicity; and c) although lead exposure has largely declined in the United States over the past 10 to 15 years, decades of heavy environmental pollution have resulted in significant accumulation of lead in bone among most members of the general U.S. population. Epidemiologic research on the impact of lead stored in bone is now possible with the development of 109Cd K-X-ray fluorescence (KXRF) instruments for the in vivo measurement of lead in bone. In this paper, the KXRF method will be briefly reviewed, followed by a summary of several Superfund-supported studies (and others) of blood lead and KXRF-measured bone lead in which these measures are compared as biologic markers of lead dose. Measurement of bone lead in epidemiologic studies has proved useful in exposure assessment studies, i.e., in identifying factors that contribute most to retained body lead burden, and in investigating cumulative lead exposure as a risk factor for poor health outcomes such as hypertension, kidney impairment, cognitive impairment, behavioral disturbances, and adverse reproductive outcomes.”
Heavy metals accumulation affects bone microarchitecture in osteoporotic patients. “In conclusion, the presence of heavy metals into bone shed new light on the comprehension of the pathogenesis of osteoporosis since these elements could play a non redundant role in the development of osteoporosis at cellular/molecular and epigenetic level.”
An analysis of factors affecting the mercury content in the human femoral bone. “The research showed that the mercury content of bones can be associated with body mass index, differences in body anatomy, and gender.”
Factors affecting the aluminium content of human femoral head and neck. “The study showed that the content of aluminium in the head and neck of the femur depends on the factors such as: type of medicines taken, contact with chemicals at work, differences in body anatomy and sex. The study on the levels of aluminium in bones and the factors affecting its concentration is a valuable source of information for further research on the role of aluminium in bone diseases.”
Cumulative lead exposure and tooth loss in men: the normative aging study. “Individuals previously exposed to lead remain at risk because of endogenous release of lead stored in their skeletal compartments. However, it is not known if long-term cumulative lead exposure is a risk factor for tooth loss . . . Long-term cumulative lead exposure is associated with increased odds of tooth loss.”
Calcium supplement: humanity’s double-edged sword. “The principle aim of the present study is to investigate the dark side of calcium, pollutions in calcium preparation especially lead (Pb), mercury (Hg) and cadmium (Cd). The collected samples were the different calcium salts in the market and 18 preparations which were classified into 3 groups: Calcium carbonate salts, Chelated calcium and natural-raw calcium. All samples were analyzed for lead, cadmium and mercury by inductively Coupled Plasma Mass Spectrometry (ICP-MS) technique, in house method based on AOAC (2005) 999.10 by ICP-MS. The calcium carbonate and the natural-raw calcium in every sample contained lead at 0.023-0.407 mg/kg of calcium powder. Meanwhile, the natural-raw calcium such as oyster, coral and animal bone showed amount of lead at 0.106-0.384 mg/kg with small amounts of mercury and cadmium. The chelated calcium such as calcium gluconate, calcium lactate and calcium citrate are free of lead.”
The feasibility of in vivo quantification of bone-fluorine in humans by delayed neutron activation analysis: a pilot study. “Fluorine is stored almost completely in the skeleton making bone an ideal site for measurement to assess long-term exposure.”
Regulation and Isoform Function of the V-ATPases. “Immunolocalization studies of islet cells from these mice suggest that the a2 isoform may compensate for the loss of a3 in acidifying the insulin-containing compartment, but a2 appears unable to replace a3 in its role in insulin secretion. The a3 isoform is also expressed in the adrenal, parathyroid, thyroid and pituitary glands, and in immature melanosomes, where it functions to keep this organelle acidic.”
The Metallothionein-Null Phenotype Is Associated with Heightened Sensitivity to Lead Toxicity and an Inability to Form Inclusion Bodies. “Therefore, the purpose of the present study was to investigate the role of MT in lead toxicity using genetically engineered systems. Initial studies used MT-null mice that are unable to produce the major forms of MT (MT-I and MT-II isoforms) and compared them to WT controls. Despite accumulating less renal lead, MT-null animals were significantly more sensitive than WT mice to the nephrotoxic effects of lead, as assessed by nephromegaly, renal function, and molecular evidence of a toxic response. Surprisingly, MT-null mice did not form inclusion bodies. Additional work in vitro showed MT-null cells similarly accumulated less lead but were still more sensitive to lead-induced cytotoxicity than WT cells. MT-null cells also did not form inclusion bodies after lead exposure, although they were common in WT cells. These data indicate that MT may play a role in lead toxicity and, possibly, in inclusion body formation. In addition, because the inability to produce MT seems to be related to enhanced susceptibility to lead toxicity, individuals that poorly express MT may have increased susceptibility to lead intoxication . . . What is perhaps more important is that this study predicts that individuals less able to produce MT may be hypersensitive to lead intoxication, indicating a potential genetic basis for lead sensitivity. It is clear that genetic polymorphisms exist in the human MT genes, although how these polymorphisms might affect lead toxicity is unknown.”
Analysis of lead toxicity in human cells. “In an attempt to find changes in gene expression following exposures to lead, we identified genes whose expressions were induced by lead and remained activated even after the lead was removed from the media. The most pronounced effect was the activation of the expression of metallothionein (MT) genes. MT gene expression has been identified and utilized as a biomarker of heavy metal exposures in a variety of biological systems including in human cell lines as well as in exposures to cadmium in humans. Our findings imply that expressions of metallothionein genes in human tissues also may be applied to assessing exposures to lead.”
Maternal bone lead as an independent risk factor for fetal neurotoxicity: a prospective study. “Higher maternal trabecular bone lead levels constitute an independent risk factor for impaired mental development in infants at 24 months of age. This effect is probably attributable to mobilization of maternal bone lead stores, a phenomenon that may constitute a significant public health problem in view of the long residence time of lead in bone.”
Role of metallothionein 2A polymorphism on lead metabolism: Are pregnant women with a heterozygote genotype for metallothionein 2A polymorphism and their newborns at risk of having higher blood lead levels? “In this study, we have demonstrated for the first time that maternal metallothionein 2A -5 A/G SNP is significantly associated with maternal blood lead concentrations, thus suggesting that pregnant women with AG genotype for MT2A polymorphism might have high blood lead levels and their newborns may be at risk of low-level cord blood lead variation even at environmental lead exposure . . . MT is one of the most important bivalent metal-binding proteins and is known to be protective against the toxicity of many metals, including lead. “
Fetal and postnatal metal dysregulation in autism. “Genetic and environmental factors contribute to the etiologies of autism spectrum disorder (ASD), but evidence of specific environmental exposures and susceptibility windows is limited. Here we study monozygotic and dizygotic twins discordant for ASD to test whether fetal and postnatal metal dysregulation increases ASD risk. Using validated tooth-matrix biomarkers, we estimate pre- and post-natal exposure profiles of essential and toxic elements. Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD. Independent replication in population-based studies is needed to extend these findings.”