In this article the authors (Luthe and Bischoff, 2020) connect recent findings in nano-toxicology with the investigations in Ludwig van Beethoven’s supposed saturnism. Namely, contradicting measurements of lead concentration in Beethoven’s hair and bone cannot be explained by the current hypothesis discussed among scientists. This mismatch may be called the key to the conundrum. It is also of broader interest to toxicologists, as the circumstances of Beethoven’s poisoning elucidate a general issue of particle uptake and resulting effects, which is quite neglected until now. They suggest that lead containing micro- and nanoparticles, i.e. lead oxides and acetate are the basis for the contradicting lead levels. The different portal of entry discriminates the concentrations in the bones when compared to the hair follicles. The authors also consider the source for these ultrafine lead-containing particles in Beethoven’s environment, and propose a complete explanation for his saturnism. 

 

Beethoven’s saturnism conundrum solved:

High lead levels in hair and low levels in bones result from micro and nano sized lead particle uptake

submitted Dec-12-2019, accepted Nov-23-2020, published Dec-22-2020

Gregor Luthe1, 2* , Matthias Bischoff 3

1Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, 100 Oakdale Campus, Iowa City, IA 52242, USA

2WindplusSonne GmbH, Fabrikstrasse 3, D-48599 Gronau, Germany

3Luftkurholz B.V., Bultsweg 90, 7532 XJ Enschede, The Netherlands

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Manuscript as PDF:

LUTHE_2020_Beethoven-s_saturnism_conundrum_solved_NANOBAY.pdf

 

Abstract

It was given that Beethoven drank too much Hungarian wine, sweetened with lead sugar (lead acetate), in addition his physicians used lead-containing salve. The lead should have poisoned him. However, recent analysis has shown that the salves contained ammonium, not lead. Further, an analysis of his hair showed high amounts of lead, while deep in his bones the lead concentrations were comparatively normal for the time and age. This apparent contradiction cannot be explained by the prevailing hypotheses discussed among scientists. 

A review of the musical and medical literature was done. The literature on exposure and excretion involving micro- and nanoparticles of metal oxides was studied and compared. In particular, occupational related lead poising was studied. The discrepancy of findings was investigated by combining data about the relation of particle size and deposition in the lung – the lung as a major route of exposure – with data about penetration of ultrafine particles into hair follicles.

It has been reported recently that ultrafine titanium dioxide particles may enter the hair follicles by a non-invasive pathway, peaking at a penetration depth of 1200 mm for a particle size of 643 nm. This is the case for lipophilic, as well as for hydrophilic model particles. The source of the ultrafine lead-containing particles in Beethoven’s environment could be due to lead corrosion, resulting from the destruction and disintegration of entire organ flutes and other instruments made out of lead alloys. This corrosion produced lead-containing fine particles.

We consider that lead containing particles, i.e. lead oxides and acetate are the basis of the Beethoven saturnism conundrum. The different portals of entry – lung and follicle – discriminates the concentrations in the bones compared to the hair. Lead corrosion is triggered by acetic and formic acid fumes from wood, especially oak in wet and cold places. More than 10,000 organs in central Europe exhibit this phenomenon. We think that this corrosion is the key to Beethoven’s hearing loss and eye problems. 

 

 

Keywords

Saturnism, Beethoven, micro and nano lead containing particles, non invasive transdermal delivery, hair follicles, TiO2, stratum covenum, respiratory tract, lead oxidation, organ pipes

 

Introduction

Findings of unusually high amounts of lead in Beethoven’s preserved hair [1] form the center argument for the post-mortem diagnosis of lead poisoning as the cause of his illness, assumed to be so-called saturnism. Four-hundred twenty-two hairs were the pool for the investigations. After first measurements, high levels of lead in his bones were also reported [2]. The DNA of both – hair and bone – match, leaving no doubt about the identity of the samples. Scientists concluded that Beethoven poisoned himself with cheap Hungarian wine, which was often sweetened with lead sugar [3]. A second hypothesis rests on lead poisoning by lead-rich medicines. The poisoning effects of such salves were known at Beethoven’s time. However, the wounds in his abdomen were closed with lead containing creams to prevent inflammation [3,4], which was given priority over longtime poisonous effects. Third, scientists speculate that the drinking cures from special healing fountains, which Beethoven frequented during his many stays in health resorts, could have been the reason [4-6]. Forth, lead poisoning by fish consumption was suggested [3,5,6]. However, there are no other cases known in Vienna from the time.

All this might be true. However, some contradictory findings cannot be explained by the routes of exposure and excretion mentioned above:

 (i) Research by Todd (2011) revealed that – in contrast to the earlier findings – the lead level in Beethoven’s skull was not higher than that of many others persons of his age and time [7]. The prior findings of high levels of lead were measured just on the surface. However, a poisoning by lead sugar would have resulted in high amounts throughout bone, where 99% of lead is stored [8]. Therefore, the prior findings can be considered invalidated.

(ii) The non-equal distribution of lead with high peaks inside his hair, which indicates different levels of exposure over time. Poisoning from regularly consumed wine containing lead sugar would have resulted in an equal distribution [1].

(iii) Contradicting results from measurements in the bone and the hair. Normal values of lead in his bones were found, while the hair has high amounts. According to everything known about lead uptake, this not possible in the same person. However, as mentioned above the DNA of both samples match and the contradicting results build a conundrum yet unsolved.

The dispute, therefore, about his alleged lead poisoning continues. In this article, we will propose a hypothesis explaining the mismatches described. In addition to the scientific interest, we do this also to fulfil his wish to find an explanation for this suffering and make it public. In his Heiligstadt testament Beethoven pleaded for an answer to the cause of his suffering [9] as the world would also judge him and his opus on this.

 

Saturnism in humankind and artists

Saturnism (lead poisoning) in humans has been present throughout history. Lead-rich pigments were used in prehistoric cave paintings [3]. The Romans produced nearly 60,000 metric tons of lead annually over 400 years and poisoned themselves [10]. Lead was omnipresent in the Roman world in cookware, water pipes, sweeteners of food, preservative, additive in wines, makeup/cosmetics, and construction of roofs, to mention only some applications. For patricians – in contrast to plebeians, who could not afford wine sweeteners – the lead uptake is estimated to have been 1 mg/day [11]. In modern times, lead uptake could also be very high; estimations claim that 1980 US citizens were exposed to 0.3 mg/day [11]. 

The medical implications of lead uptake were known in ancient Rome: Slaves carried out mining, because the mining process made for discomfort and caused disorders [12]. Interestingly, the mining of lead was forbidden in Italy at the end of the Roman Empire, but continued legally in the provinces. Some historians even consider saturnism as the major cause for the fall of the empire [12].

In the middle ages the so-called “prince of physicians” Avicenna (980-1037) earned this title at the early age of 17 by identifying lead as the cause of disease of a prominent patient. Avicenna had been called to assist Ibn Manus, the samanid emir of Bukhara (now Uzbekistan) in his efforts to save the emirs life. He discovered that the emir suffered heavily from lead poisoning, caused by pigments of a goblet he routinely used for drinking [13]. In the 15th century Paracelsus called saturnism the “miners disease”.  As early as 1498 some states in the Holy Roman Empire of the German Nation imposed a ban on the addition of lead sweeteners in wine and punished violators with pain and death [14]. Nevertheless, lead sweetening and poisoning of wine continued. King Georg’s II, doctor, Sir George Baker, discovered with the support of Benjamin Franklin the so-called colic of Devonshire [15]. This colic was associated with palsy, encephalopathy, anemia and abdominal pains and was lethal. Sometimes lead was added involuntarily. It was found that the lead contamination of wine resulted from the presses used to crush the grapes, which lost material during the processing. Madeira wine was known for its sweetness, unfortunately caused by the lead instruments producing it [14]. In modern times, the failure of John Franklin’s expedition to discover the Northwest Passage cost the lives of 128 men between 1845 and 1848, presumably due to the consumption of food stored in casks sealed with lead [16]. More recently, red lead oxide was mixed with paprika powder to enhance the color for the use in ice cream production in India, which resulted in a severe epidemic [3]. In Nigeria, soil contamination resulted in thousands of childhood deaths [3].

No wonder that saturnism is very well known to have afflicted geniuses of our societies as well. Famous artists, especially painters have been diagnosed with a work-related occupational exposure to lead, examples are Rubens, Goya, Fortuny, van Gogh, Renoir, Dufy, Klee, Frida Kalho, Porttinari [3]. Besides Beethoven, Händel’s gout attacks have also been attributed to saturnine gout [17]. He was a heavy drinker of wines from Porto and Madeira, which were put through presses with leaden surfaces and were fortified with alcohol distilled in lead pipes. 

 

 

Results

Explaining the mismatch in lead concentrations in hair and bones

It has been hypothesized that Beethoven’s symptoms are consistent with saturnism. However, the specifics of Beethoven’s live do not fit completely and the mismatch between high lead concentrations inside the hair and normal concentrations inside the bones directly contradicts this long held belief.  The DNA of the hair and the bone samples match. We do not want to dispute that the hair and the bones belonged to Beethoven. Even if this were not the case, i.e.if the samples belong to a different person, there is a mismatch in the findings that need to be solved. We consider the cause for the mismatch to be the key to the conundrum, and to be of broader interest to toxicologists.

The source of the lead in the hair could have been of irregular nature. Alternatively, the route of exposure could discriminate the exposure of the blood, resulting in lower levels in bones, compared to the uptake in the hair. It is also of note that the exposure must have been fluctuating with definite peaks [5]. Further, the uptake and excretion must have occurred in an unusual way [8]. The lead levels in samples of Beethoven’s skull were not higher than those of many others persons of his age and time. Previous reports of high lead concentrations seem to be based on incorrect analyses. The high values were only measured on the surface of a bone but not inside. The lead contamination on the surface can have different causes, for example topically applied lead containing medications like salves. A post-mortem lead exposure of the bone could also be the reason. This is a quest for another article. Here, we propose an explanation for the data mismatch, and exclude an atypical high exposure of Beethoven to lead sugar through wine consumption to be the relevant one. This would have resulted in high levels in the entire bone, where 99% of lead is stored. Same results would be found with other lead sources as food, portable and mineral water, oral, medications and topically-applied creams to prevent inflammation of wounds.

Non-invasive delivery of lead containing micro- and nano-particles to hair follicles

In 2008 Lademann et al. found that the hair follicles play an important role in the non-invasive transdermal penetration process of topically applied TiOmicro- and nanoparticles [18]. The researchers studied the penetration of TiO2 micro particles into the stratum corneum on pig ears. On the first glance, it seemed implausible that topically applied substances only penetrate into the hair follicles, especially during a mass flow from the inside to the outside, i.e.hair growth and sebum production. The results showed this to happen and also, they could demonstrate that this is the case for lipophilic and hydrophilic micro particles. TiO2 micro- and nanoparticles are generally applied as models to study up-take, distribution and excretion of particular matter in biological systems [19]. The uptake via hair follicles and their reservoir function is currently under investigation as an efficient carrier for drug delivery [18-20]. The hair follicle is the organ producing hair. The growth of the hair occurs in phases, including growth (anagen), cessation (catagen) and rest (telogen). In each phase lead can be embedded in the hair via micro sized particles of oxide, sulfide and acetate. These are deposited on the stratum corneum, the outermost skin layer. For these compounds the pathway through the follicles seems to constitute no barrier. This is also the case for nano sized analogues. See figure 1 for the distribution of the particular matter in the follicles.

Figure 1: (A) Distribution of the particular matter into the follicles in a schematic presentation. (B) Particle size determines deposition in lung and penetration depth in hair follicle. In hair follicles penetration is highest for particles of a size ~ 643 nm with a depth of ~ 1200 µm.Figure 1: (A) Distribution of the particular matter into the follicles in a schematic presentation. (B) Particle size determines deposition in lung and penetration depth in hair follicle. In hair follicles penetration is highest for particles of a size ~ 643 nm with a depth of ~ 1200 µm.

 

Size dependency of the deposition of ultra fine particles in the lung 

Ultrafine particles may enter the body via the respiratory system. There is growing body of research based on to the hypothesis that airborne ultra fine particles cause significant health effects. Oberdoerster et al. [21] describes the up-take of ultra fine particles as size dependent due to the efficient deposition and disposition of inhaled ultra fine particles. There are size dependent differences in the clearance. The fractional deposition is different according to size in the nasopharyngeal, tracheobronchial and alveolar regions of the human respiratory tract. Particles of 1 nm are deposited by diffusion and are mainly deposited by nasal pharyngeal laryngeal deposition contributes with over 90 %. The tracheobronchial deposition is highest for particles of 5 nm and the alveolar deposition for particles of 10 nm. The total minimum of deposition is reached for particles with 200 nm (see figure 1 B) and increases again to a peak at 5 mm mainly on nasal deposition based on sedimentation and impaction. Importantly, nano sized particles appear to translocate readily to extra pulmonary sites and reach other target organs by different transfer routes and mechanism. These mechanisms involve transcytosis across epithelia of the respiratory tract to the interstitium, access to the blood circulation, as well as uptake by sensory nerve endings embedded in airway epithelia. For water-soluble particles like lead acetate, solvation plays a major role once the particle is deposited.  Lead deposits in the bones via blood circulation. 

 

 

Discussion

It is our hypothesis that Beethoven was

  1. exposed to micro- and nanoparticles of lead oxide, sulfide and/or acetate 
  2. the uptake of these particles was non-invasive transdermal, delivered to and stored at hair follicles resulting in a high lead level inside the hair 
  3. the uptake via the respiratory tract was small compared to ii and resulted in a lower body burden of lead concentrations in the bones 

Origin of lead containing micro- and nanoparticles

If one accepts the hair follicle pathway as route of lead uptake in Beethoven’s case, the question of the source remains. The usual candidates of oral consumption and skin application seem unlikely for head exposure. The source suggested in the present article is quite specific for Beethoven’s profession. Exposure to lead micro particles can be the result of lead corrosion in organ pipes – called “Bleifrass” in German [22]. 

From a general chemical perspective, lead becomes grey by oxidation to lead(II)-oxid (PbO) and lead hydroxide (Pb(OH)2). The final one reacts with carbon dioxide (CO2) of the air to form basic lead(II)-carbonate (Pb(OH)2 . 2 PbCO3). This process protects the metallic lead against further corrosion. In the presence of chloride and sulfur it reacts to form PbCl2 (DH -359 kJmol-1) and PbS (DH -94 kJmol-1) in exergonic reactions [22]. In the presence of acids, like phosphoric acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, formic acid, and acetic acid, the metallic lead forms thin layers of these salts, called plumbates. Organic acids emitted from the wood of organ cases are corrosive agents for lead-rich pipes [23, 24]. Historical organs all over Europe – more than 10,000 suffer from corrosion [25]. For an example of lead corrosion of organ pipes see Figure 2. There are very severe cases sometimes destroying entire organs,e.g. in Lübeck Germany one organ originating from 1637 and completed by F. Stellwagen. 

 

 

Figure 2: Corrosion of an organ, showing lead oxidation, “Bleifraß”. Picture by Sabine Schmithals, CC BY 3.0, https://commons.wikimedia.org/wiki/File:Orgelpfeife_mit_Bleikorrosion.jpg, https://creativecommons.org/licenses/by/3.0/deed.en.Figure 2: Corrosion of an organ, showing lead oxidation, “Bleifraß”. Picture by Sabine Schmithals, CC BY 3.0, https://commons.wikimedia.org/wiki/File:Orgelpfeife_mit_Bleikorrosion.jpg, https://creativecommons.org/licenses/by/3.0/deed.en.

 

When a pipe corrodes it will gradually develop cracks and holes before it finally collapses. There is no way to solve the problem the historic pipes have to be replaced with modern ones [25]. The ambient air in European churches is characterized by low temperature and relative high humidity and the presence of large numbers of wooden structures, which emit small amounts of acids of the types described above. As early as 1778, Watson reported the connection between lead corrosion and volatile acids from oak beams [26]. Especially the windchest contains high amounts of wood and results in bigger corrosion effects. Recent studies from 2013 of the COLLAPSE project, entitled “Corrosion of organ pipes - causes and recommendations”, show that mainly acetic acid and formic acid contribute to the corrosion. Measurements demonstrated that values of up to 1437 ppm for acetic acid could be found in the pallet box of the organ in Oegstgeest, The Netherlands [27]. X-ray diffraction (XRD) analyses showed clearly that the predominant crystalline corrosion products are lead white (Pb(CO3)2(OH)2, hydrocerussite), lead formatted hydroxide (Pb(HCOO)OH) and plumbonacrite (Pb10O(OH)6(CO3)6 [25, 27]. Particles of a-SiOwere found as well [25]. Very surprisingly, ion chromatography of exposed metal coupons demonstrated significantly high amounts of acetate (74 mg/cm2) and formate (93 mg/cm2) accumulated on the pure lead (Oegstgeest, The Netherlands).  In 2016, Oertel and Richards could identify organic lead crystals [22]. Interestingly, for pipes with a percentage of 2 % tin, this is not the case [22]. This explains as well why not every device from lead shows this phenomenon, as the right amount of tin seems to be a very effective protection.

With more than 10,000 organs showing lead corrosion, especially in cold and humid areas like Germany and Austria, it seems reasonable to consider that Beethoven could have been exposed to lead emitted by some of them. This would also explain the peak exposures in Beethoven’s hair. In addition, lead corrosion is also known in harpsichords and pianos [28], and is a problem on old instruments today. As Beethoven was forced by his father to practice the harpsichord a lot in his childhood, this is another possible route of exposure. 

Our hypothesis is that Beethoven was exposed to micro- and nanoparticles of lead, enhanced by particular acetates, when playing the harpsichord and especially the organ, or playing or conducting music in proximity to the pipes. In these cases the vibrations of the music result in an ablating process of the corroded lead surfaces. Hereby the lead salts become airborne and can distribute themselves. Hair with its high surface and fatty layer is a perfect sponge for collecting airborne micro- and nanoparticles from the air. Human hair grows with different speeds and different lengths. The average rate of hair growth is about 1.25 cm/month, or about 15 cm/year [29]. Considering Beethoven’s hair length with 30-40 cm, his hair collected the exposure to lead for the 2 to 3 years before he died. We consider that during this time Beethoven was in several churches exposed to those particles.

Aside from organ pipes, other exposure sources might be considered, e.g. cabinets (285-4600 ppm acetic acid, and 175-850 ppm formic acid [30]), pine wood shelfs, oak wood planks (65-379 ppm acetic acid, and 33-270 ppm formic acid [31]), pianos, storage rooms (n.d.-195 ppm acetic acid, and n.d.- 53 ppm [32]). One should note, the starting concentrations in fresh wood are higher compared to old wood [25].

Saturnism

These findings cannot finally clarify if Beethoven suffered under Saturnism or if he suffered under Paget's disease of bone, an affliction of the cycle of bone renewal and repair [33]. Paget's disease of bone occurs typically localized and could have deformed bones, leading to blocked sound waves or impaired nerves. The present article focuses on the mismatch of the lead concentrations in hair versus bones, as major point of interest for the lead poisoning hypothesis.

 

 

Conclusion 

In this article, we conclude that the mismatch of high non-regular lead values inside the Beethoven’s hair and the normal concentration of lead inside his bones are due to lead exposure of micro- and nanoparticles, taken up by the hair follicles. This uptake route could be dominant compared to the uptake via the respiratory tract. The hair-bone mismatch seems illogical on first glance – as the hair is considered a reliable library of the exposure to all kind of compounds. DNA analysis stated clearly that the DNA of both samples (hair and bone) match. Aside the interest for Beethoven, this mismatch puts forward a fundamental methodological question. It is a clear indication that we were not aware of an important portal of entry and a very specific behavior of lead in terms of excretion and deposition. For this the Beethoven case has a much wider impact. In this way Beethoven’s case assisted us in finding an answer on this bigger picture. For the elucidation of the mismatch we focused on the special environment of Beethoven. The phenomenon of “Bleifraß” and the results of very recent studies made us aware that a particular kind of lead exposure could be the key. Studies of lipophilic and hydrophilic nano and micro model – particular TiO2 particles – demonstrates that the hair follicles are a non-invasive transdermal portal of entry, for the up-take and storage of particular micro- and nanoparticles. Once entered into the hair follicle, the water-soluble lead acetate particles dissolve and can be built into the hair. We identify the differences by the size of the particles in deposition in the respiratory tract [34] on one site and the depth of the penetration into the hair follicle on the other as the reason for the mismatch of the found concentrations of lead in the hair versus the bones, see figure 1.  

This topic demonstrated how results of applied cultural research and material chemistry can lead to new insights in fundamental (nano)toxicology.

In a follow-up article, we will investigate further the basis of the development of Beethoven’s deafness by exposure to micro- and nano-lead particles as well as other medical implications, like his neuro impairments and eye-illness. Also, we will discuss the ear as potential portal of entry.

 

 

List of abbreviations

TiO2: titanium dioxide

PbO: lead(II)-oxid

Pb(OH)2: lead hydroxid

CO2: Carbon dioxid

Pb(OH)2 . 2 PbCO3: lead(II)-carbonate

PbCl2: lead(II) chloride 

PbS: lead(II) sulphide

Pb(CO3)2(OH)2: hydrocerussite, lead white

Pb(HCOO)OH: lead formatted hydroxide

Pb10O(OH)6(CO3)6: plumbonacrite

 a-SiO2: alpha phase of silicon dioxide, a-quartz

 

Authors' contributions

GL conceived the idea. GL and MB analysed and interpreted the literature, drafted and revised the paper. Both authors have approved the final manuscript.

 

Acknowledgements

We would like to thank Megan and Hein van Gills for correction of the manuscript. Larry Robertson and Gabriele Ludewig, my warm Humboldt hosts I wish to thank for their excellent training in toxicology. The Rotary Euregio Club Gronau I thank for stimulating discussion around the saturnism during a visit paid at the Beethoven house in Bonn. My friends made me aware of this scientific riddle. We would like to thank the Saxion University of Applied Sciences and the Tech For Future fund, an initiative of the Saxion and Windesheim Universities of Applied Sciences and the regional government of Overijssel, The Netherlands for friendly support.

 

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