Revision 63600f43-018f-46cb-9b54-fa142903cacc

It's not the "heavy" that makes a metal toxic. Lithium and Beryllium are considerably lighter but still toxic to humans. If the metals interact negatively within the human body, it is considered toxic. For e.g. Lead disrupts the functions of the digestive system, nervous system, respiratory system, reproductive system. In addition, it prevents enzymes from performing their normal activities. Lead even disrupts the normal DNA transcription process and causes disability in bones. Lead as such has no physiological role in the body and even smaller levels of lead can cause toxicity.

You can refer to below studies for more information:

 1. Mahdi Balali-Mood,Kobra Naseri, Zoya Tahergorabi, Mohammad Reza Khazdair, Mahmood Sadeghi, *Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and Arsenic*, . Pharmacol., **2021** DOI: [10.3389/fphar.2021.643972][1]
 2. Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN. *Toxicity, mechanism and health effects of some heavy metals*. Interdiscip Toxicol. **2014**; 7(2):60-72. doi: [10.2478/intox-2014-0009][2] 
 3. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. *Heavy metal toxicity and the environment*. Exp Suppl. **2012**;101:133-64. doi: [10.1007/978-3-7643-8340-4_6][3]


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I should add more on what "actually" makes lead toxic to humans. Please see this simplified diagram:

[![enter image description here][4]][4]

([Image source][5])

I'll go by each routes:

 - Route 1: [Lead is known to have a strong affinity towards sulfur][6]. In human body, sulfur exists in the form of thiols.  So, lead tries to bind with thiol group<sup>1</sup> leading to major implications. 
 - Route 2: Lead is able to produce free radical and reactive oxygen species (ROS) via **Fenton-Haver-Weiss pathway**<sup>2</sup> possible by stimulating NADPH oxidases or by competing for the metal binding site of an enzyme/protein (Route 3) or by attacking the thiols moiety of protein (Route 1). The mechanism is below:
[![enter image description here][7]][7]

     It causes a destructive behavior known as [oxidative stress][8]. One of the major implication of oxidative stress is lead-induced hypertension and cardiovascular diseases<sup>3</sup> 
 - Route 3: Lead is known to mimic calcium because they share similar properties (In its +2 cationic form, lead has a radius of 132 pm while the calcium cation has a radius of 106 pm. In their elemental forms, lead has a radius of 175 pm and calcium has a radius of 197 pm). And that is the reason, lead compete with calcium and substitutes calcium from cells, tissues and enzymatic sites. One of the major effect is on calmodulin which is a calcium binding protein and lead will try to replace calcium inhibiting phosphorylation of brain membranes<sup>4</sup>.

There are other diagrams which which shows the mechanistical and pathological effect of lead in human body like [this][9] and [this][10] (the latter one shows the effect in DNA, RNA and lipids)

**References:**

 1. Magyar JS, Weng TC, Stern CM, Dye DF, Rous BW, Payne JC, Bridgewater BM, Mijovilovich A, Parkin G, Zaleski JM, Penner-Hahn JE, Godwin HA. *Reexamination of lead(II) coordination preferences in sulfur-rich sites: implications for a critical mechanism of lead poisoning*. J Am Chem Soc. **2005** 127(26):9495-505. doi: [10.1021/ja0424530][11]
 2. Kehrer JP. *The Haber-Weiss reaction and mechanisms of toxicity. Toxicology*. **2000** Aug 14;149(1):43-50. doi: 1[0.1016/s0300-483x(00)00231-6][12] 
 3. *Mechanisms of lead-induced hypertension and cardiovascular disease*, Nosratola D. Vaziri, American Journal of Physiology-Heart and Circulatory Physiology **2008** 295:2, H454-H465, DOI: [10.1152/ajpheart.00158.2008][13]
 4. Habermann E, Crowell K, Janicki P. *Lead and other metals can substitute for Ca2+ in calmodulin.* Arch Toxicol. **1983** Sep;54(1):61-70. doi: [10.1007/BF00277816][14] 
 5. https://sites.tufts.edu/leadpoisoning/pathways/lead-and-calcium/
 6. FHW pathway mechanism image source: *Trace Metals in the Environment* by Daisy Joseph, **2023** 

  [1]: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.643972/full
  [2]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427717/
  [3]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144270/
  [4]: https://i.sstatic.net/M6Jal9cp.png
  [5]: https://www.researchgate.net/figure/Figure-depicting-the-mechanisms-of-lead-toxicity-It-can-thus-be-concluded-that-inhibitory_fig4_6313819
  [6]: https://chemistry.stackexchange.com/questions/71734/why-do-heavy-metals-like-mercury-and-lead-have-an-affinity-for-sulfur-or-sulfur
  [7]: https://i.sstatic.net/oTmaNfHA.png
  [8]: https://en.wikipedia.org/wiki/Oxidative_stress
  [9]: https://Pb%20toxicity%20causes%20oxidative%20stress%20by%20reactive%20oxygen%20species%20(ROS)%20production%20and%20depletion%20of%20antioxidant%20enzymes.
  [10]: https://www.semanticscholar.org/paper/Molecular-mechanisms-of-lead-toxicity-Szymanski/2eac0c763e0efc5057617c30b826534b41ec8a32
  [11]: https://pubmed.ncbi.nlm.nih.gov/15984876/
  [12]: https://pubmed.ncbi.nlm.nih.gov/10963860/
  [13]: https://journals.physiology.org/doi/full/10.1152/ajpheart.00158.2008
  [14]: https://pubmed.ncbi.nlm.nih.gov/6314931/